Cohort Study Subodh S Gupta Dr. Sushila Nayar School of Public Health MGIMS, Sewagram.

Cohort StudyCohort Study

Subodh S Subodh S GuptaGupta

Dr. Sushila Nayar Dr. Sushila Nayar School of Public School of Public

HealthHealthMGIMS, SewagramMGIMS, Sewagram

Type of studyType of study Alternate nameAlternate name Unit of Unit of studystudy

Observational studiesObservational studiesDescriptive studiesDescriptive studies

Analytical studiesAnalytical studies EcologicalEcological CorrelationalCorrelational PopulationsPopulations

Cross-sectionalCross-sectional PrevalencePrevalence IndividualsIndividuals

Case-ControlCase-Control Case-ReferenceCase-Reference IndividualsIndividuals

CohortCohort Follow-up/ Follow-up/ LongitudinalLongitudinal

IndividualsIndividuals

Experimental/ intervention StudiesExperimental/ intervention Studies Randomized Randomized Controlled Controlled Studies Studies

Clinical TrialClinical Trial PatientsPatients

Field TrialField Trial Healthy personHealthy person

Community TrialCommunity Trial Community intervention Community intervention studiesstudies

CommunitiesCommunities

Origin of word ‘cohort’Origin of word ‘cohort’

► The word ‘cohort’ has The word ‘cohort’ has its origin in the Latin its origin in the Latin ‘‘cohorscohors’’

► ‘‘cohorscohors’’ (Latin word) = (Latin word) = Refers to warriors and Refers to warriors and gives notion of a group gives notion of a group of persons proceeding of persons proceeding together in timetogether in time

►Group of persons with Group of persons with a common statistical a common statistical characteristic; e.g. characteristic; e.g. age, birth dateage, birth date

Definition & SynonymsDefinition & SynonymsDefinitionDefinition “ “The cohort study is an observational The cohort study is an observational

epidemiological study which, after epidemiological study which, after the manner of an experiment, the manner of an experiment, attempts to study the relationship attempts to study the relationship between a purported cause between a purported cause (exposure) and the subsequent risk (exposure) and the subsequent risk of developing disease.”of developing disease.”

SynonymsSynonyms ►Follow-upFollow-up►LongitudinalLongitudinal►ProspectiveProspective► Incidence studyIncidence study

►Groups are exposure based:Groups are exposure based: The group or The group or groups of persons to be studied… are groups of persons to be studied… are defined in terms of characteristics manifest defined in terms of characteristics manifest prior to the appearance of the disease under prior to the appearance of the disease under investigation investigation

► The study is conceptually longitudinal:The study is conceptually longitudinal: The The study groups so defined are observed over a study groups so defined are observed over a period of time to determine the frequency of period of time to determine the frequency of disease among themdisease among them

► A definite beginning and endA definite beginning and end

The cohort designThe cohort design


►Efficient for examining When there is good evidence of exposure When there is good evidence of exposure

and disease. and disease. When exposure is rare but incidence of When exposure is rare but incidence of

disease is higher among exposeddisease is higher among exposed When follow-up is easy, cohort is stableWhen follow-up is easy, cohort is stable When ample funds are availableWhen ample funds are available Common outcomes


►Many different outcomes for same exposure►The dynamic nature of many risk factors The dynamic nature of many risk factors

and their relations in time to disease and their relations in time to disease occurrence can be captured here (cannot occurrence can be captured here (cannot be done in cross-sectional study and only be done in cross-sectional study and only with difficulty in case-control study)with difficulty in case-control study)

►Associations (not cause and effect)►Estimate incidence within risk factor groups

Cannot estimate prevalence of risk factor

TimeTime

Direction of Direction of enquiryenquiry

Population

Cases (People

with disease)

Exposed

Not exposed

Exposed

Not exposed

Controls (People

without disease)

Case control studyCase control study

TimeTime

Population

People without

the outcome

Exposed

Not Exposed

Diseased

Not diseased

Diseased

Not diseased


Cohort studyCohort study

Types of cohort studyTypes of cohort study

►Historical/ Retrospective/ Non-concurrent Historical/ Retrospective/ Non-concurrent ►Prospective/ ConcurrentProspective/ Concurrent

The distinction between retrospective The distinction between retrospective and prospective cohort studies is and prospective cohort studies is important, not because of any important, not because of any conceptual difference or differences in conceptual difference or differences in interpretability of findings, but because interpretability of findings, but because of relevance to some practical issues, of relevance to some practical issues, mostly the ability to control confounding.mostly the ability to control confounding.

TimeTime

Population

People without

the outcome

Exposed

Not Exposed

Diseased

Not diseased

Diseased

Not diseased


Point in time when enquiry Point in time when enquiry begins?begins?

Population

People without

the outcome

Exposed

Not Exposed

Diseased

Not diseased

Diseased

Not diseased

TimeTimeDirection of Direction of

enquiryenquiry

Both exposures and outcomes Both exposures and outcomes measured prospectivelymeasured prospectively

Population

People without

the outcome

Exposed

Not Exposed

Diseased

Not diseased

Diseased

Not diseased

Exposures measured Exposures measured retrospectively and outcomes retrospectively and outcomes

prospectivelyprospectively


enquiryenquiry

Population

People without

the outcome

Exposed

Not Exposed

Diseased

Not diseased

Diseased

Not diseased

Both exposures and outcomes Both exposures and outcomes measured retrospectivelymeasured retrospectively


enquiryenquiry

AdvantagesAdvantages►Direct estimate of risk and rate of disease Direct estimate of risk and rate of disease

occurrence over timeoccurrence over time► An efficient means of studying rare exposuresAn efficient means of studying rare exposures► Assess multiple outcomes of a single exposureAssess multiple outcomes of a single exposure► Establish temporal relationship between Establish temporal relationship between

exposure and outcomeexposure and outcome► Exposure definitely precedes the outcomeExposure definitely precedes the outcome► Avoids recall bias, survival biasAvoids recall bias, survival bias►Does not require strict random assignments of Does not require strict random assignments of

subjectssubjects► Can be done with original data or secondary Can be done with original data or secondary

datadata

Best observational design to Best observational design to establish associationestablish association

DisadvantagesDisadvantages

► Very large sample sizes, especially for rare Very large sample sizes, especially for rare outcomesoutcomes

► Expensive and time-consumingExpensive and time-consuming► Attrition problem (Loss to follow-up)Attrition problem (Loss to follow-up)►Differences in the quality of measurement of Differences in the quality of measurement of

exposure or disease b/w the cohorts may exposure or disease b/w the cohorts may introduce misclassification (information introduce misclassification (information bias)bias)

► Can not infer causal relationCan not infer causal relation► Very specific findingVery specific finding► Complexity of data analysisComplexity of data analysis► Ethical issuesEthical issues► Study effectsStudy effects

Alternate designs and Alternate designs and concernsconcerns

►Two separate cohorts; exposed and Two separate cohorts; exposed and unexposed subjectsunexposed subjects

►Omission of non-factor groupOmission of non-factor group►Use of external comparisonUse of external comparison►Use of mortality than morbidity as Use of mortality than morbidity as

outcomeoutcome►Event notification arises from routine Event notification arises from routine

statistics, rather than special statistics, rather than special observationsobservations

►Comparison of several groupsComparison of several groups►Competing causes of deathCompeting causes of death

Cohort Study: StepsCohort Study: Steps

1.1. Identification of study population Identification of study population and initial stepsand initial steps

2.2. Measurement of exposureMeasurement of exposure

3.3. Selection of study and Selection of study and comparison cohortscomparison cohorts

4.4. Follow-up (for outcome Follow-up (for outcome measurement)measurement)

5.5. Data analysisData analysis

Steps in conducting cohort Steps in conducting cohort studystudy

Types of cohortsTypes of cohorts►Closed or fixed cohorts: Closed or fixed cohorts:

Fixed group of persons followed from a Fixed group of persons followed from a certain point in time until a defined endpoint certain point in time until a defined endpoint

Starting point - exposure defining event Starting point - exposure defining event Endpoint – occurrence of the disease, loss to Endpoint – occurrence of the disease, loss to follow-up, deathfollow-up, death

The exposure is an event which occurs only The exposure is an event which occurs only once once

►Open or dynamic cohorts:Open or dynamic cohorts: Subjects may enter or leave the study at Subjects may enter or leave the study at

any time any time Exposure status may change over timeExposure status may change over time

CohortsCohorts

►General population cohorts:General population cohorts: population population groups offering special resources for groups offering special resources for follow-up or data linkage are chosen, and follow-up or data linkage are chosen, and the individuals are subsequently allocated the individuals are subsequently allocated according to their exposure statusaccording to their exposure status

►Special exposure cohorts:Special exposure cohorts: Samples chosen Samples chosen on the basis of a particular exposureon the basis of a particular exposure

Exposures may be a particular event, a Exposures may be a particular event, a permanent state or a reversible statepermanent state or a reversible state

General population cohorts General population cohorts (groups offering special (groups offering special

resources)resources)►Groups with readily available health Groups with readily available health

recordsrecords►Certain professional categoriesCertain professional categories►Obstetric populationsObstetric populations►Volunteer groupsVolunteer groups►Geographically identified cohortsGeographically identified cohorts►Record linkageRecord linkage

Special exposure cohortsSpecial exposure cohorts (groups offering special (groups offering special

resources) resources) ►Exposed to certain factor or eventExposed to certain factor or event►Occupational groupsOccupational groups►Based on qualitative characteristicsBased on qualitative characteristics

Population-based Cohort Population-based Cohort StudiesStudies

AdvantagesAdvantages►Estimation of distributions and Estimation of distributions and

prevalence rates of relevant variablesprevalence rates of relevant variables►Risk factor distributionsRisk factor distributions► Ideal setting in which to carry out Ideal setting in which to carry out

unbiased evaluation of relationsunbiased evaluation of relations

Selection of comparison groupSelection of comparison group

► Internal comparisonInternal comparison Only one cohort identifiedOnly one cohort identified Later on, classified into study and comparison Later on, classified into study and comparison

cohort based on exposurecohort based on exposure

► External comparisonExternal comparison More than one cohort identified More than one cohort identified e.g. Cohort of radiologist compared with e.g. Cohort of radiologist compared with

ophthalmologistsophthalmologists

► Comparison with general population ratesComparison with general population rates If no comparison group is available we can If no comparison group is available we can

compare the rates of study cohort with general compare the rates of study cohort with general populationpopulation

Cancer rate of uranium miners with cancer in Cancer rate of uranium miners with cancer in general populationgeneral population

Ideal CohortIdeal Cohort

►Stable cohort Stable cohort ►Cooperative cohortCooperative cohort►Committed cohortCommitted cohort

►Well informed cohortWell informed cohort

Exposure measurementExposure measurement

►Exposures: exogenous and/ or Exposures: exogenous and/ or endogenousendogenous Reference periodReference period Frequency of follow-upFrequency of follow-up

►Challenge of prospective data collectionChallenge of prospective data collection Changes in instrument over timeChanges in instrument over time Use of repeated measuresUse of repeated measures Data collection costsData collection costs

Sources of informationSources of information

► RecordsRecords► Cohort members: self-administered Cohort members: self-administered

questionnaires, interviews, telephone questionnaires, interviews, telephone interviews, mailed questionnaires, interviews, mailed questionnaires,

►Medical examination & biomarkers: Clinic Medical examination & biomarkers: Clinic examinations & lab testsexaminations & lab tests

►Measures of the environment: level of air Measures of the environment: level of air pollution, quality of drinking water, airborne pollution, quality of drinking water, airborne radiationradiation

►Multiple methodsMultiple methods

Discrete eventsDiscrete events ► Single eventsSingle events

MortalityMortality First occurrence of a disease or health-related First occurrence of a disease or health-related

outcomeoutcome

►Multiple occurrencesMultiple occurrences Disease outcomeDisease outcome Transition between states of health/ diseaseTransition between states of health/ disease Transitions between functional statesTransitions between functional states

►Level of a markerLevel of a marker

Follow-up: Types of Follow-up: Types of outcomesoutcomes

Exercise 1Exercise 1►An investigator wants to discover whether or

not being overweight in adolescence increases the risk of cardiovascular mortality in adulthood.

a) Assuming historical records are available, would a prospective or retrospective study be more practical?

b) Who would comprise the investigator's cohort under study?

c) Who would comprise the investigator's exposed and unexposed groups in this cohort?

Group Exercise Group Exercise ►Design a Cohort Study ►Outline the steps which you will require to do

for this study►Special efforts you may need to do for follow-

up of the study subjects►What care you will need to take to reduce

measurement bias►Calculate the sample size

Challenges in Challenges in conducting Cohort conducting Cohort

StudyStudy

Challenge 1:Challenge 1: multiple dimensions of time in cohort multiple dimensions of time in cohort

studystudy

AgeAge

Calendar periodCalendar period

Exposure 1Exposure 1

Exposure 2Exposure 2

Exposure iExposure i

Covariate 1Covariate 1

Covariate 2Covariate 2

Covariate iCovariate iStart of Start of

studystudyEnd of End of studystudy

►Loss to follow-upLoss to follow-up DropoutsDropouts Can not be tracedCan not be traced

►More concern: those who cannot be More concern: those who cannot be traced; May have moved because they traced; May have moved because they have developed the diseasehave developed the disease

Challenge 2:Challenge 2:Retaining cohort study membersRetaining cohort study members

Effect of NonresponseEffect of Nonresponse

►Nonresponse: a major problemNonresponse: a major problem►A differential nonresponse will distrorts A differential nonresponse will distrorts

the true relationship b/w exposure and the true relationship b/w exposure and outcomeoutcome

Nonresponse: random or Nonresponse: random or selective?selective?

►Exposure data: find out if Exposure data: find out if nonrespondents are different from the nonrespondents are different from the respondents respondents Intensive efforts within the study designIntensive efforts within the study design Follow-up of the nonrespondents as well Follow-up of the nonrespondents as well

as respondentsas respondents

Challenge 3:Challenge 3:Large Modern Cohort StudiesLarge Modern Cohort Studies

►Huge requirements of resources and Huge requirements of resources and manpowermanpower

►Management of huge databaseManagement of huge database► Follow-upFollow-up► Exposure informationExposure information►Data quality?Data quality?► Collection of biologic samples?Collection of biologic samples?

Challenge 4:Challenge 4:Long term follow-upLong term follow-up

►Operational problemsOperational problems►Cumulative risk getting closer to oneCumulative risk getting closer to one

Cohort Study AnalysisCohort Study Analysis

Standard 2 X 2 tableStandard 2 X 2 table(Relation between exposure and (Relation between exposure and

outcome)outcome)

DISEASE DISEASE STATUSSTATUS

PresenPresent t

AbsentAbsent TotalTotal

EXPOSUREXPOSURE STATUSE STATUS

PresentPresent aa bb a + ba + b

AbsentAbsent cc dd c + dc + d

TotalTotal a + ca + c b + db + d NN

Two types of measures for Two types of measures for raterate

►Cumulative incidence = Proportion of Cumulative incidence = Proportion of study subjects getting the outcome study subjects getting the outcome during the study periodduring the study period

► Incidence rate = New cases/ Person-Incidence rate = New cases/ Person-time under observationtime under observation

Number of Number of newnew cases of disease cases of disease occurring over a specified period occurring over a specified period of time in a population at risk. of time in a population at risk.

1. Cumulative incidence rate:

EXAMPLEEXAMPLE

A surveillance system for Hospital A surveillance system for Hospital acquired infection among the post-acquired infection among the post-operative patients in a month. operative patients in a month.

ExampleExample

0 5 10 15 20 25 30

9

61414

24

1914

45

1921

6

Number of Number of newnew cases of disease cases of disease occurring over a specified period occurring over a specified period of time in a population at risk of time in a population at risk throughout the intervalthroughout the interval..

2. Incidence density:

Incidence density requires us to Incidence density requires us to add up add up the period of time each individual was the period of time each individual was present in the population, and was at riskpresent in the population, and was at risk of becoming a new case of disease. of becoming a new case of disease.

Incidence density characteristically uses Incidence density characteristically uses as the denominator as the denominator person-years at risk.person-years at risk. (Time period can be person-months, days, (Time period can be person-months, days, or even hours, depending on the disease or even hours, depending on the disease process being studied.)process being studied.)

USES OF INCIDENCE DENSITY AND USES OF INCIDENCE DENSITY AND CUMULATIVE INCIDENCECUMULATIVE INCIDENCE

► Incidence density gives the best Incidence density gives the best estimate of the estimate of the true risktrue risk of acquiring of acquiring disease at any moment in time. disease at any moment in time. ► Cumulative incidence gives the Cumulative incidence gives the best estimate of best estimate of how many people how many people will eventually get the diseasewill eventually get the disease in an in an enumerated population.enumerated population.

Standard 2 X 2 tableStandard 2 X 2 table(Relation between exposure and (Relation between exposure and

outcome)outcome)

Peripheral Vascular DiseasePeripheral Vascular Disease

PresenPresent t


Cigarette Cigarette SmokingSmoking

PresentPresent 1515 17121712 17271727

AbsentAbsent 4141 31883188 32293229

TotalTotal 5656 49004900 49564956

l X 2 tablel X 2 table(Relation between exposure and (Relation between exposure and

outcome)outcome)

Disease statusDisease status

PresenPresent t


Cholesterol Cholesterol quintilesquintiles

11stst 1515 798798 813813

22ndnd 2020 794794 814814

33rdrd 2626 791791 817817

44thth 4141 785785 826826

55thth 4848 777777 825825

TotalTotal 150150 39453945 40954095

Comparing risks in different Comparing risks in different groupsgroups

►Relative risk OR Risk ratio (RR)Relative risk OR Risk ratio (RR)►Attributable risk OR Risk difference Attributable risk OR Risk difference

(AR)(AR)►Attributable risk percent (AR%)Attributable risk percent (AR%)►Population attributable risk (PAR)Population attributable risk (PAR)►Population attributable risk percent Population attributable risk percent

(PAR%)(PAR%)►Odds Ratio (OR)Odds Ratio (OR)

Relative risk OR Risk ratioRelative risk OR Risk ratio

►Ratio of the risk among exposed to the risk Ratio of the risk among exposed to the risk among unexposed among unexposed [Risk (Exp) / Risk (Unexp)][Risk (Exp) / Risk (Unexp)]

►Risk of disease among exposed Risk of disease among exposed = = [a/ [a+ b)] [a/ [a+ b)]

►Risk of disease among unexposed Risk of disease among unexposed = = [c/ [c [c/ [c +d)] +d)]

►RR = RR = [a/ [a +b)] / [c/ [c +d)][a/ [a +b)] / [c/ [c +d)]►For null hypothesis, Risk ratio will equal For null hypothesis, Risk ratio will equal

‘one’‘one’►SE=SE=

Risk difference vs. Relative Risk difference vs. Relative riskrisk

191

8.7

0

20

40

60

80

100

120

140

160

180

200

Abs

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SmokersNon smokers

Rela

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Ab

solu

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k

Attributable risk OR Risk Attributable risk OR Risk difference difference (Absolute differences in (Absolute differences in

risks or rates)risks or rates)► Also known as attributable riskAlso known as attributable risk► Risk (Exp) – Risk (Unexp)Risk (Exp) – Risk (Unexp)► Risk of disease among exposed = Risk of disease among exposed = [a/ [a +b)] [a/ [a +b)] ► Risk of disease among unexposed = Risk of disease among unexposed = [c/ [c [c/ [c

+d)] +d)] ► Risk difference = Risk difference = [a/ [a +b)] - [c/ [c +d)][a/ [a +b)] - [c/ [c +d)]► For null hypothesis, Risk difference will For null hypothesis, Risk difference will

equal ‘zero’equal ‘zero’

Risk difference vs. Relative Risk difference vs. Relative riskrisk

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Attributable risk percent among Attributable risk percent among exposedexposed

►Among exposed, what percent of the total Among exposed, what percent of the total risk for disease is due to the exposurerisk for disease is due to the exposure

►AR% (Exposed) AR% (Exposed)

= = [Risk (Exp) – Risk (Unexp)]/ Risk (Exp) X [Risk (Exp) – Risk (Unexp)]/ Risk (Exp) X 100100

= (RR – 1)/ RR X 100= (RR – 1)/ RR X 100

= (OR – 1)/ OR= (OR – 1)/ OR X 100X 100 (if risk is small)(if risk is small)

191

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Attributable Risk PercentAttributable Risk Percent

Attributable Risk PercentAttributable Risk Percent191

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Attributable risk Percent = (RR-1)/ RR Attributable risk Percent = (RR-1)/ RR *100*100

Population attributable riskPopulation attributable risk

► In the general population, how much of In the general population, how much of the total risk for disease is due to the the total risk for disease is due to the risk factorrisk factor

►Risk (Total) – Risk (Unexp)Risk (Total) – Risk (Unexp)►Risk (Total) Risk (Total) = [Proportion population Exp X Risk (Exp)] += [Proportion population Exp X Risk (Exp)] +

[Proportion population Unexp X Risk [Proportion population Unexp X Risk (Unexp)](Unexp)]

Population attributable risk Population attributable risk percentpercent

►Among the general population, what Among the general population, what percent of the total risk for disease is percent of the total risk for disease is due to the risk factordue to the risk factor

►PAR% PAR%

= = [Risk (Total) – Risk (Unexp)]/ Risk (Total) X [Risk (Total) – Risk (Unexp)]/ Risk (Total) X 100100

= [Pe (RR – 1)]/ [1+ Pe (RR – 1)] X 100= [Pe (RR – 1)]/ [1+ Pe (RR – 1)] X 100

0

20

40

60

80

100

120

140

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Smoker Nonsmoker

(RR-1)(1-Pe)Pe(RR-1)

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Population attributable risk Population attributable risk percentpercent

Population Attributable risk Percent Population Attributable risk Percent = [Pe (RR – 1)]/ [1+ Pe (RR – 1)] X 100 = [Pe (RR – 1)]/ [1+ Pe (RR – 1)] X 100

RR

1

Risk ReductionRisk Reduction

► Risk (T/t) = Risk (T/t) = a/(a+b)a/(a+b)► Risk (Exp) = cRisk (Exp) = c/(c+d)/(c+d)► RR = RR = Risk (T/t)/ Risk (Exp)Risk (T/t)/ Risk (Exp)► ARR = ARR = Risk (Exp) – Risk (T/t)Risk (Exp) – Risk (T/t)► RRR = RRR = [Risk (Exp) – Risk (T/t)] / Risk (Exp)[Risk (Exp) – Risk (T/t)] / Risk (Exp)

= 1-Risk(T/t)/Risk(Exp)= 1-Risk(T/t)/Risk(Exp) = 1-RR= 1-RR

►NNT = 1/ARRNNT = 1/ARR = 1/Risk(Exp)*RRR= 1/Risk(Exp)*RRR►NNHNNH

Analytical considerationsAnalytical considerations

►Concurrent follow-upConcurrent follow-up►Varying follow-up datesVarying follow-up dates►Moving baseline datesMoving baseline dates►WithdrawalsWithdrawals►Competing causes of deathCompeting causes of death

Analytical considerationsAnalytical considerations► Concurrent follow-upConcurrent follow-up

Simple risk-based analysesSimple risk-based analyses Survival analysisSurvival analysis

► Varying follow-up datesVarying follow-up dates Simple risk analysis for all events up to, but not Simple risk analysis for all events up to, but not

exceeding, the minimum elapsed timeexceeding, the minimum elapsed time Survival analysisSurvival analysis

►Moving baseline datesMoving baseline dates Ignore and measure elapsed time since Ignore and measure elapsed time since

recruitmentrecruitment Survival analysisSurvival analysis

►WithdrawalsWithdrawals► Competing causes of failureCompeting causes of failure

Advanced methodsAdvanced methods

►StandardizationStandardization►StratificationStratification►Life TablesLife Tables►Multivariate analysis and Cox Multivariate analysis and Cox

regressionregression

Exercise 2Exercise 2►A cohort study to explore the relationship

between visual impairment and the risk of injuries from falls among the elderly.

►A total of 400 visually impaired (VI) persons >70 yrs are compared against 400 controls without VI.

►Over a 5-year follow-up period, 80 VI persons and 20 non-VI persons have injuries from falls.

a) Construct a 2x2 table from the information above

b) Calculate the followings with their CIwith their CI : Cumulative Incidence rate for exposed and

unexposed Relative risk Attributable risk & Attributable risk percent

Exercise 3Exercise 3

►A retrospective cohort study to explore A retrospective cohort study to explore the relationship between perimenopausal the relationship between perimenopausal exogenous estrogen use and the risk of exogenous estrogen use and the risk of coronary heart disease (CHD). coronary heart disease (CHD).

►A total of 5000 exposed and 5000 A total of 5000 exposed and 5000 unexposed women are enrolled and unexposed women are enrolled and followed for 15 years for the development followed for 15 years for the development of myocardial infarction (MI). of myocardial infarction (MI).

►A total of 200 estrogen users and 300 A total of 200 estrogen users and 300 nonusers had MIs.nonusers had MIs.

a)a) The risk (CI) of a MI among estrogen The risk (CI) of a MI among estrogen users users

b)b) The risk (CI) of a MI among nonusers The risk (CI) of a MI among nonusers of estrogenof estrogen

c)c) The relative risk (CIR) for MI The relative risk (CIR) for MI

d)d) Based on the results of this study is Based on the results of this study is estrogen use a causative or estrogen use a causative or protective factor for MI?protective factor for MI?

Exercise 3 (Contd.)Exercise 3 (Contd.)

Exercise 4Exercise 4

Shaper et. al. (1988) Shaper et. al. (1988) ► A random sample of 7729 middle-aged A random sample of 7729 middle-aged

British menBritish men► Each man asked, at baseline, his alcohol Each man asked, at baseline, his alcohol

consumption consumption ►Next 7.5 years, death certificates collected Next 7.5 years, death certificates collected

for any subject who diedfor any subject who diedAlcohol consumption group (Unit/wk)None Occasion

al (<1)Light (1-15)

Moderate (16-42)

Heavy (>42)

Subjects

466 1845 2544 2042 832

Deaths 41 142 143 116 62

a)a) Calculate the risk and the relative risk Calculate the risk and the relative risk for each alcohol consumption group.for each alcohol consumption group.

b)b) Why might the conclusion based on Why might the conclusion based on the above table may be misleading? the above table may be misleading? Given adequate funding, describe Given adequate funding, describe how? how?


Exercise 5Exercise 5► In a cohort study of 34387 menopausal women in In a cohort study of 34387 menopausal women in

Iowa, intakes of certain vitamins were assessed in Iowa, intakes of certain vitamins were assessed in 1986. In the period up to the end of 1992, 879 of 1986. In the period up to the end of 1992, 879 of these women were newly diagnosed with breast these women were newly diagnosed with breast cancer. The table below shows data for two cancer. The table below shows data for two vitamins, classified according to ranked categories vitamins, classified according to ranked categories of intake.of intake. Vitamin C Vitamin E

Events PY Events PY

1 (low) 507 124,373 570 143,117

2 217 57,268 129 33,950

3 76 19,357 71 19,536

4 55 17,013 28 6,942

5 (high) 24 7,711 81 22,176

a)a) For each vitamin, calculate the For each vitamin, calculate the relative rates (with 95% confidence relative rates (with 95% confidence intervals) taking the low-consumption intervals) taking the low-consumption group as the base. Do your results group as the base. Do your results suggest any beneficial (or otherwise) suggest any beneficial (or otherwise) effect of additional vitamin C or E effect of additional vitamin C or E intake?intake?


Types of biasTypes of bias

►Selection biasSelection bias►Follow-up biasFollow-up bias► Information biasInformation bias►Confounding biasConfounding bias►Post hoc biasPost hoc bias

Selection biasSelection bias►Group studied does not reflect the Group studied does not reflect the

same distribution of factors (such as same distribution of factors (such as age, sex, SES, behavior etc.) as occurs age, sex, SES, behavior etc.) as occurs in the general populationin the general population Effect of volunteeringEffect of volunteering Whole spectrum of independent variables Whole spectrum of independent variables

not represented in the study groupnot represented in the study group Presence of incipient diseasePresence of incipient disease Distribution of covariates Distribution of covariates Survival cohorts: cohorts ascertained long Survival cohorts: cohorts ascertained long

after exposureafter exposure

►Also known as ‘Migration Bias’Also known as ‘Migration Bias’► In nearly all large studies some In nearly all large studies some

members of the original cohort drop members of the original cohort drop out of the studyout of the study

► If drop-outs occur randomly, such that If drop-outs occur randomly, such that characteristics of lost subjects in one characteristics of lost subjects in one group are on an average similar to group are on an average similar to those who remain in the group, no bias those who remain in the group, no bias is introducedis introduced

►But ordinarily the characteristics of the But ordinarily the characteristics of the lost subjects are not the samelost subjects are not the same

Follow-up biasFollow-up bias

Example of ‘lost to follow-Example of ‘lost to follow-up’up’

++ -- TotalTotal

++ 5050 100100 150150

--

1000100000

2000200000

3000300000

EXPOSUREirradiation

++ -- TotalTotal

++ 6060

--

40004000 80008000 1200012000

30 30

EXPOSUREirradiation

DISEASE

cataract

RR= 50/10000 100/20000 = 1

RR= 30/4000 30/8000 = 2

Example…. ‘healthy worker Example…. ‘healthy worker effect’ effect’

►QuestionQuestion: association b/w : association b/w formaldehyde exposure and eye formaldehyde exposure and eye irritationirritation

►SubjectsSubjects: factory workers exposed to : factory workers exposed to formaldehydeformaldehyde

►BiasBias: those who suffer most from eye : those who suffer most from eye irritation are likely to leave the job at irritation are likely to leave the job at their own request or on medical advicetheir own request or on medical advice

►ResultResult: remaining workers are less : remaining workers are less affected; association effect is dilutedaffected; association effect is diluted

Measurement / (Mis) Measurement / (Mis) classificationclassification

►Exposure misclassificationExposure misclassification occurs occurs when exposed subjects are incorrectly when exposed subjects are incorrectly classified as unexposed, or vice versaclassified as unexposed, or vice versa

►Disease misclassificationDisease misclassification occurs when occurs when diseased subjects are incorrectly diseased subjects are incorrectly classified as non-diseased, or vice classified as non-diseased, or vice versaversa

Misclassification bias: Misclassification bias: due to measurement errorsdue to measurement errors

►Systematic biasSystematic bias►Measurement errorsMeasurement errors

Non-differential:Non-differential: observed relative risk observed relative risk biased towards the null hypothesis biased towards the null hypothesis

Differential:Differential: This can lead to study results, This can lead to study results, which can not be interpreted because the which can not be interpreted because the observed relative risk may be biased observed relative risk may be biased towards the null, away from the null, or towards the null, away from the null, or cross over the null value compared with the cross over the null value compared with the true relative risktrue relative risk

Sources of measurement Sources of measurement errorserrors

► Selection/ design of the instrument to measure Selection/ design of the instrument to measure the exposurethe exposure

►Omissions in the protocol for use of the Omissions in the protocol for use of the instrumentinstrument

► Poor execution of the study protocolPoor execution of the study protocol► Inherent subject characteristicsInherent subject characteristics►Drift in accuracy of exposure measures over Drift in accuracy of exposure measures over

timetime►Data processing and creation of exposure Data processing and creation of exposure

variablesvariables

Reassignment to exposure Reassignment to exposure categorycategory

► Changes in dichotomous exposure, if not Changes in dichotomous exposure, if not taken into consideration will tend to make taken into consideration will tend to make the strength of an observed association the strength of an observed association lower than that which actually existedlower than that which actually existed Latency is likely to be shortLatency is likely to be short Exposure accumulates over time during the studyExposure accumulates over time during the study Very accurate results desirableVery accurate results desirable

► Reassignment may not be possibleReassignment may not be possible Close cohort as a ruleClose cohort as a rule Latency is very longLatency is very long Duration of follow-up is very longDuration of follow-up is very long

Separate examination of outcome in those Separate examination of outcome in those who changed exposure status during the who changed exposure status during the studystudy

Confounding biasConfounding bias

►Other factors which are associated Other factors which are associated with both outcome and exposure with both outcome and exposure variables do not have the same variables do not have the same distribution in the exposed and distribution in the exposed and unexposed groupunexposed group

Examples … confoundingExamples … confounding

COFFEE DRINKING HEART DISEASE

SMOKING

(Coffee drinkers are more likely to smoke)

(Smoking increasesthe risk of heart ds)

Resolving Confounding BiasResolving Confounding Bias

►StandardizationStandardization►StratificationStratification►Multivariate adjustmentMultivariate adjustment

Post hoc biasPost hoc bias

►Use of data from a cohort study to Use of data from a cohort study to make observations that were not part make observations that were not part of original study intent. of original study intent.

Thank you

7/13/2007 PRD-91

Internal & External validityInternal & External validity

Cohort Study Subodh S Gupta Dr. Sushila Nayar School of Public Health MGIMS, Sewagram.

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