Advanced course in field epidemiology

Health Protection Surveillance Centre Ireland

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Objectives To strengthen understanding of various epidemiological studies available in field epidemiology James Stuart & Alain Moren, June 2006

Presentations on methods

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Study design Reference group Counfounding and effect modification Matching Mesures or impact Alternative designs Introduction to multivariable analysis How to interpret data How to make an oral scientifi presentation

Case studies

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Smoking and lung cancer Trichinosis Toxic shock syndrom Tiramisu

Presentations from participants

One each day Evening session?

Epidemiological studies Two types

Observation Experiment

James Stuart & Alain Moren, June 2006

Experiment

Exposure assigned Exposed Not exposed Disease occurrence Unethical to perform experiments on people if exposure is harmful

If exposure not harmful Treatment Preventive measure (vaccination) R andomised C ontrolled T rial Blinded Doses Time period Risk - effect No bias If not possible Left with observation of experiments designed by Nature Cohort studies Case control studies

Cohort studies

marching towards outcomes

What is a cohort?

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One of 10 divisions of a Roman legion Group of individuals

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sharing same experience followed up for specified period of time

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Examples

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birth cohort cohort of guests at barbecue

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occupational cohort of chemical plant workers EPIET cohort 10

follow-up period

end of follow-up

Calculate measure of frequency:

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Cumulative incidence

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Incidence proportion

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Attack rate (outbreak)

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Incidence density

Cohort studies

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Purpose

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Study if an exposure is associated with outcome(s)?

Estimate risk of outcome in exposed and unexposed cohort Compare risk of outcome in two cohorts

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Cohort membership

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Being at risk of outcome(s) studied Being alive and free of outcome at start of follow-up

exposed

Cohort studies

unexposed

exposed

Cohort studies

Incidence among exposed unexposed Incidence among unexposed

Presentation of cohort data: 2x2 table

ill not ill 49 49 98 ate ham did not ham 4 6 10

Presentation of cohort data: Population at risk

Does HIV infection increase risk of developing TB among a population of drug users?

HIV + HIV Population Cases (f/u 2 years) 215 8 289 1 Source: Selwyn et al., New York, 1989

Presentation of cohort data: Person-years at risk

Tobacco smoking and lung cancer, England & Wales, 1951 Person-years Cases Smoke 102,600 133 Do not smoke 42,800 3 Source: Doll & Hill

Presentation of data: Various exposure levels

Daily number of cigarettes smoked Person-years at risk Lung cancer cases > 25 15 - 24 1 - 14 none 25,100 38,900 38,600 42,800 57 54 22 3

Prospective cohort study

Exposure Study starts Disease occurrence Study starts Exposure Disease occurrence

time time

Retrospective cohort studies Exposure Disease occurrence Study starts

time

Recipe: Cohort study

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Identify group of

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exposed subjects unexposed subjects

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Follow up for disease occurrence Measure incidence of disease Compare incidence between exposed and unexposed group

Our objective is to compare:

an incidence rate in an exposed population to the rate that would have been observed in the same population, at the same time if it had not been exposed

Principle of case control studies

Source population Exposed Unexposed

Source population Exposed Unexposed

Cases

Source population Exposed Unexposed Sample

Cases Controls

Source population Exposed Unexposed Sample Cases Controls = Sample of the denominator Representative with regard to exposure Controls

Intuitively if the frequency of exposure is higher among cases than controls then the incidence rate will probably be higher among exposed than non exposed.

Case control study

Exposure ?

?

Disease Controls Retrospective nature

Distribution of cases and controls according to exposure in a case control study Exposed Not exposed Total % exposed Cases a c a + c a/(a+c) Controls b d b + d b/(b+d)

Distribution of myocardial infarction cases and controls by oral contraceptive use Oral contraceptives Yes No Total % exposed Myocardial Infarction 693 307 1000 69.3% Controls 320 680 1000 32 %

Distribution of myocardial infarction cases and controls by amount of physical activity Physical activity >= 2500 Kcal < 2500 Kcal Total % exposed Myocardial Infarction 190 176 366 51.9% Controls 230 136 366 62.8 %

Volvo factory, Sweden, 3000 employees, Cohort study 200 cases of gastroenteritis Water Consumption YES NO Total Cases 150 50 200 Controls ?

?

200

Two types of case control studies

Exploratory New disease New risk factors Several exposures "Fishing expedition" Analytical Precise a single hypothesis Dose response

exposed

Cohort studies

Incidence among exposed unexposed Incidence among unexposed

Effect measures in cohort studies

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Absolute measures

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Risk difference (RD) I e - I ue

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Relative measures

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Relative risk (RR) Rate ratio Risk ratio I I e ue I e = incidence in exposed I ue = incidence in unexposed

ate ham did not eat ham ill not ill Incidence 49 49 98 50 % 4 6 10 40 % Risk difference 50% - 40% = 10% Relative risk 50% / 40% = 1.25

Does HIV infection increase risk of developing TB among drug users?

Exposure HIV + HIV - Population (f/u 2 years) 215 298 Cases 8 1 Incidence (%) 3.7 0.3 Relative Risk 11

Vaccine efficacy (VE)

Status Pop. Vaccinated Unvaccinated 301,545 298,655 Total 600,200 Cases Cases per 1,000 150 515 0.49 1.72 RR 0.28 Ref. 665 1.11 = 72% VE = 1 - RR = 1 - 0.28

Various exposure levels

Exposure level High Medium Low Population Cases Incidence at risk N 1 N 2 N 3 a a a 1 2 3 I I I 1 2 3 Unexposed N ne c I ue

Exposure level High Medium Low

Various exposure levels

Population Cases Incidence RR at risk N 1 N 2 N 3 a a a 1 2 3 I I I 1 2 3 RR RR RR 1 2 3 Unexposed N ne c I ue Reference

Cohort study: Tobacco smoking and lung cancer, England & Wales, 1951 Cigarettes smoked/d > 25 15 - 24 1 - 14 none Source: Doll & Hill Person-years at risk Cases Rate per 1000 p-y Rate ratio 25,100 38,900 38,600 42,800 57 54 22 3 2.27 1.39 0.57 0.07 32.4 19.8 8.1 Ref.

A cohort study allows to calculate indicators which have a clear, precise meaning.

The results are immediately understandable.

Cohort studies Rate Rate difference Rate Ratio (strength of association) Case control studies No calculation of rates Proportion of exposure Any way of estimating Rate ratio ?

E Cases Population denominator a P 1 E c P 0 I 1 = a / P 1

}

I 1 / I 0 = ----- a /P 1 c /P 0 I 0 = c /P 0 Cases Population sample E a P 1 /10 E c P 0 /10 I 1 = a ------- P 1 / 10 c I 0 = ------- P 0 /10

}

I 1 / I 0 = ----- a /P 1 c /P 0

Source population Cases Pop.

E a E c P 1 P 0 I 1 = a / P 1

}

I 1 / I 0 = ----- a /P 1 c /P 0 I 0 = c /P 0 E Cases a E c = sample Controls b P 1 -- P 0 b = --- d d

Source population Cases Pop.

E a P 1 I 1 = a / P 1 E E c c E Cases a d P 0 b = sample Controls P 1 I 0 = c /P 0 b

}

I 1 / I 0 a /P 1 a . P 0 a . d = ------ = ------- = ----- = a / c ----- c /P 0 c . P 1 c . b b / d Since d/b = P 0 / P 1 -- = --- P 0 d

Case control study design Cases Controls E a b Odds ratio a --- c b -- d = a x d --- --- b x c E c d

Radiation Exp Breast cancer Total Cases Rate RR

28010 41 14.6

1.9

Unexp.

19017 15 7.9

Ref.

Source: Rothman

Radiation Exp Breast cancer Total Cases Rate RR

28010 41 14.6

1.9

Controls OR

280 1.9

Unexp.

19017 15 7.9

Ref.

190 Ref.

Source: Rothman

Distribution of myocardial infarction in cases and controls by recent oral contraceptive use Oral contraceptives Yes No Total % exposed Myocardial Infarction 693 307 1000 69.3% Controls 320 680 1000 32 % OR 4.8

Ref.

Distribution of myocardial infarction in cases and controls by amount of physical activity Physical activity >= 2500 Kca l < 2500 Kcal Total % exposed Myocardial Infarction 190 176 366 51.9% Controls 230 136 366 62.8 % OR 0.64

Ref.

Distribution of cases of endometrial cancer by estrogen use Estrogen use Cases Controls Odds ratio High a1 b1 a1d/b1c Low None a2 c b2 d a2d/b2c Reference

Relation of Hepatocellular Adenoma to duration of oral contraceptive use in 79 cases and 220 controls Months of OC use Cases Controls Odds ratio 0-12 13-36 37-60 61-84 >= 85 Total 7 11 20 21 20 79 Source: Rooks et al. 1979 121 49 23 20 7 220 Ref.

3.9

15.0

18.1

49.7

Limitations of case-control studies

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Cannot compute directly relative risk Not suitable for rare exposure Temporal relationship exposure-disease difficult to establish

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Biases +++

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control selection recall biases when collecting data

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Loss of precision due to sampling

Disadvantages of cohort studies

Large sample size Latency period Lost to follow Exposure can change Multiple exposure = difficult Ethical considerations Cost Time consuming

Advantages of case control studies

Rare diseases Several exposures Long latency Rapidity Low cost Small sample size Available data No ethical problem

Strengths of cohort studies

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Can directly measure

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incidence in exposed and unexposed groups true relative risk Well suited for rare exposure Temporal relationship exposure-disease is clear Less subject to selection biases

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outcome not known (prospective)

Strengths of cohort studies

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Can examine multiple effects for a single exposure population outcome 1 exposed N e unexposed N ne I I e1 ue1 outcome 2 I e2 I ue2 outcome 3 I e3 I ue3 RR 1 RR 2 RR 3

The cohort study is the gold-standard of analytical epidemiology

Alain Moren CASE-CONTROL STUDIES HAVE THEIR PLACE IN EPIDEMIOLOGY but if cohort study possible, do not settle for second best