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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
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
The cohort designThe cohort design
►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
Direction of Direction of enquiryenquiry
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
Direction of Direction of enquiryenquiry
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
TimeTimeDirection of Direction of
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
TimeTimeDirection of Direction of
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
AbsentAbsent TotalTotal
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
AbsentAbsent TotalTotal
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
olut
e ri
skLu
ng c
ance
r de
aths
per
10
0,00
0 ad
ult
mal
e pe
r ye
ar
SmokersNon smokers
Rela
tive ris
k
1
22
Ab
solu
te ris
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
191
8.7
0
20
40
60
80
100
120
140
160
180
200
Abs
olut
e ri
skLu
ng c
ance
r de
aths
per
10
0,00
0 ad
ult
mal
e pe
r ye
ar
SmokersNon smokersR
isk d
iffere
nce
Ab
solu
te ris
ks
(Exp
& U
nexp
)
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
8.7
0
20
40
60
80
100
120
140
160
180
200
Abs
olut
e ri
skLu
ng c
ance
r de
aths
per
10
0,00
0 ad
ult
mal
e pe
r ye
ar
Smokers Non smokers
Rela
tive ris
k
% ris
k d
ue to
exp
osu
re
1
22
Ab
solu
te ris
ks (E
xp
)
% risk due to background
Attributable Risk PercentAttributable Risk Percent
Attributable Risk PercentAttributable Risk Percent191
8.7
0
20
40
60
80
100
120
140
160
180
200
Abs
olut
e ri
skLu
ng c
ance
r de
aths
per
10
0,00
0 ad
ult
mal
e pe
r ye
ar
Smokers Non smokers
Rela
tive ris
k
p0(R
R-1
)
p0
p0RR
p0R
R
1
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
160
180
Ab
solu
te r
isk o
f lu
ng
can
cer
death
per
100,0
00 a
du
lt m
ale
per
year
Smoker Nonsmoker
(RR-1)(1-Pe)Pe(RR-1)
(1-Pe)Pe
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 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 4 (Contd.)Exercise 4 (Contd.)
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?
Exercise 5 (Contd.)Exercise 5 (Contd.)
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