epidemiological studies. experimental studies scientifically rigorous considered as natural...

Epidemiological studies

• Experimental studies • Scientifically rigorous• Considered as natural

experiments • Costly• Sometimes not feasible• Enrollment issues • Ethical issues

• Observational studies • Investigators is an

disinterested observer• People expose

themselves to the agent

• Ethical issues mitigated

Observational study - Two types

• Cohort study• Cross-sectional study

Analytical Studies

Introduction:

Analytical studies are either: • Observational Case-Control Cohort Study

• Experimental (Intervention): Animal Experiments

Human Therapeutic trials Preventive trials

Analytic Studies

• Analytic studies, etiologic studies, are performed to test specific hypothesis about a specific health problem.

• In general, associations observed in descriptive studies are often the basis for gathering more specific data and testing hypothesis in additional studies.

• Analytic studies involve the selection and comparison of two or more groups of persons, based on either their exposure or disease status…. WHY?

• To evaluate an association between exposure and disease.

• Analytic studies focuses on the magnitude of the association between the exposure and the health problem under the study.

Study Design

•Life’s a journey. . .•We each carry the burden of personal and group risk factors and exposures.•As health professionals, we hope to identify those characteristics causing disease.

Study Design

•Life’s a journey. . .•In individuals, the only way to know if a risk factor caused disease would be to find an exact double, living in a parallel universe, identical in every way to the exposed subject--except for the exposure.

Study Design

•Life’s a journey. . .•If only the exposed subject developed disease, we could be certain the exposure was causal.

Study Design

•Life’s a journey. . .•This is called the “counterfactual argument” because exact doubles and parallel universes do not exist.•(Stephen Hawking’s opinions notwithstanding. . .)•How to address this problem?

Study Design

•Life’s a journey. . .•The best we can do is compare populations that are similar (not identical) in everything except the risk factor. •If we see increased disease only in the group with the risk factor, we can suspect that the risk factor caused the disease.

Study Design

•Life’s a journey. . .•The “study base” is a population of individuals, each carrying the burden of personal and group risk factors.

•(Rothman and Greenland, Modern Epidemiology, 1998)

Cohort Study

What is a cohort?

• From Latin word Cohors, group of soldiers– 6 centuries (100 men) form a cohort, – 10 cohorts form a legion (therefore 6,000 men).

• A century, then, would correspond to a company, a cohort to a battalion, and a legion to a regiment.

– Once a cohort was formed, no new soldier were added. Soldiers remain in the same cohort for rest of service.

– Attrition occurred mainly through death

What is a cohort in epidemiology?

• A group of individuals/persons who are followed / traced over a period of time – Sharing a common characteristic or experience

• Some alternate names– Cohort study– Longitudinal study– Incidence study – Longitudinal study

Retrospective (Case-Control)

a b

dc

DISEASEpresent absentEXPOSURE

present

absent

cases

controls

Total

Total

Pro

sp

ecti

ve

(C

oh

ort

)

exposed

Not exposed

A fourfold table

Mausner, 1985

• The difference between the two types of studies lies in the way the study groups are assembled

• With either method of study, if there is a positive association between the factor and the disease:

• Those exposed will tend to develop the disease (group a),

• Those not exposed will tend not to develop it (group d).

The Prospective Approach

• The general concept of a prospective study is relatively simple.

• This type of study has been described by a variety of items: -Cohort

-Incidence-Longitudinal-Forward looking-Follow-up

Prospective Cohort “concurrent”• COHORT Study Retrospective Cohort “non-concurrent” Historical prospective

The Prospective Approach (cont.)

• 1. It starts with a group of people (a cohort) all considered to be free of a given disease.

• Information is obtained to determine persons having a particular characteristic (certain exposure) that is suspected of being related to the development of disease being investigated.

• 2. These individuals are then followed for a period of time to observe who develops/or dies from that disease

• 3. Incidence or death rates for the disease are then calculated.

The Prospective Approach (cont.)

• 4. Rates are compared for those with the characteristic and those without it.

• 5. If the rates (of development of disease) are different, an association can be said to exist between the characteristic (exposure) and the disease.

• 6. It is important to obtain information on other characteristic of the study groups: age, sex, … to account for an influence of any factors related to the disease.

Study Design

Exposure(Risk Factor)

Disease (Outcome)

+

+

_

_

Cohort Studies

• Begin with sample “Healthy Cohort” (i.e., subjects without the outcome yet)

• Start with Exposure status, then compare subsequent disease experience in exposed vs. unexposed.

Study Design


Disease (Outcome)

+

+

_

_

Case-Control Studies

• Begin with sample of “Cases and Controls”

• Start with Disease status, then assess and compare Exposures in cases vs. controls.

Study Design


Disease (Outcome)

+

+

_

_

Cross-Sectional Studies

• Begin with “Cross-sectional” sample

• Determine Exposure and Disease at same time

What is a cohort ?• A cohort is a group of persons who share a

common experience within a defined time period.

Example: • Birth cohort, marriage cohort, occupational

cohort

Cohort Study (cont.)

Essential points:• Exposed individuals in the study should be

representative of all exposed persons.

• Unexposed persons should be representative of all unexposed persons in the population.

Cohort Study (cont.)

Selection of Cohorts: several approaches• Accessible group (volunteers)• Group with available records/history of

exposure• Group experiencing some particular exposure

(arising during work)

Cohorts may be heterogeneous or homogenous

• Heterogeneous: with respect to some previous exposure as study of lung cancer and smoking.

• Homogenous in exposure:As study of the frequency of cancer among

asbestos workers. The comparison group is the general population

valuesDemonstrate excess in deaths among asbestos

workers.

Cohort studies

Intuitive approach to studying disease incidence and risk factors:

1. Start with a population at risk2. Measure characteristics at baseline3. Follow-up the population over time with

a) surveillance or b) re-examination4. Compare event rates in people with and

without characteristics of interest

Cohort studiesCan be large or smallCan be long or shortCan be simple or elaborateCan be local or multinationalFor rare outcomes need many people and/or

lengthy follow-upMay have to decide what characteristics to

measure long in advance

Community surveillance enhances generalizability of cohort findings

1. Cohort Community: compare incidence rates and characteristics of events in residents who do and who do not participate in cohort

2. Communities Cohort: compare the study community CHD experience with areas in the U.S.

COHORT STUDIES

• Cohort Study

– Key Point:–Presence or absence of risk factor is

determined before outcome occurs.

Cohort Studies

• Characteristics: follow-up period (prospective; retrospective)

• Merits: no temporal ambiguity; several outcomes could be studied at the same time; suitable for incidence estimation

• Limitations (of prospective type): expensive; time-consuming; inefficient for rare diseases; may not be feasible

• Effect measure: Risk Ratio (Relative Risk)

Coho

rt D

esig

n

time

Study begins here

Studypopulation

free ofdisease

Factorpresent

Factorabsent

disease

no disease

disease

no disease

presentfuture

Timing of cohort study

• Prospective cohort study • Retrospective cohort study • Ambidirectional cohort study

Timing of cohort study

Prospective Cohort Study Exposure

Disease

COHORT STUDIES

50% 50%

10% 90%R.F.

(+)

(-)

(+) (-)Disease Basic Idea:

See if those with the risk factor develop more disease than those without the risk factor

COHORT STUDIES

• Basic Approach: Cohort Study– Identify Cohort (s)– Measure exposure and outcome variables– Follow for development of outcomes

COHORT STUDIES

• Fixed Cohort

Exposure

(+)

(-)

x

x

x

X = outcome

Relative risk = (2/3)/(1/3) = 2.0

30 a 70 b

3 c 57 d

Salad

(+)

(-)

(+) (-)Disease = Hepatitis A

a + b 100

c + d 60

Risk =a/(a+b) =0.3

Risk =c/(c+d) = 0.05

Rel. risk=

COHORT STUDIES

aa + b

cc + d

= 0.3/0.05 =6

Fixed cohort

30 a 70 b

3 c 57 d

Salad

(+)

(-)

(+) (-)

Disease = Hep A

a + b = 100

c + d = 60

Odds Ratio: (a/c)/(b/d)=(a/b)/(c/d)

Rel. risk=

COHORT STUDIES

aa + b

cc + d

= 0.3/0.05 =6

(30/3)/(70/57)= 8.14

COHORT STUDIES•Dynamic Cohort

Exposure

(+)

(-)

Rel. Risk

= 2/3/2/3 =1

or

2/5py/2/10py

= 2.0Years

XX

XX

COHORT STUDIES

• Cohort : 16, 936 Harvard grads

• Measure: Question re: activity level

• Follow: “Sedentary”: 24 CHD deaths per 10,000 person-years

• vs. “Active”: 16 CHD deaths per 10,000 person-years

• Relative risk = 24/16 = 1.5

COHORT STUDIES

• Questions:

• Findings due to confounding?

• Could subclinical disease have affected the risk factor (activity)?

COHORT STUDIES

• Take-Home Message:• The best measure of effect is the “relative risk.”

For a fixed cohort, this will be the ratio of the cumulative incidences. For a dynamic cohort, this will be the ratio of the incidence rates.

• The odds ratio can be used for fixed cohorts comparing cumulative incidences. It will be close to the relative risk for rare diseases.

COHORT STUDIES

• Variations on a theme:

• Retrospective (Historical) Cohort

COHORT STUDIES

• Prospective: Outcomes have not yet occurred as study begins. Example: Women’s Health Study.

• Retrospective: Outcomes have already occurred as the study begins. Example: finding a trove of medical records allowing you to follow a cohort born in 1880 to death.

COHORT STUDIES

• Utility and Strengths

• Incidence and natural history

• Temporal sequence

• Avoid survivor bias

• Avoid reporting bias

• Look at multiple outcomes

Purpose of cohort study

• Descriptive – To describe the incidence of certain outcome

overtime• Analytical

– To analyze association between risk factors and outcomes

Two basic types of cohort study

• Prospective cohort • Retrospective cohort

Types of population studied

• 3 types of population – Open or dynamic– Fixed – Closed

Type Defined by Follow up Measure of disease

Open or dynamic Changeable characteristic

Members come and go, losses can occur

Incidence rate

Fixed Irrevocable event No gain in member, loses may occur

Incidence rate

Closed Irrevocable event No gain in member, no loses occur

Cumulative incidence

Open/ dynamic population

• Membership criteria is changeable – Smoking– Alcohol drinking – Certain occupation – People living in a geographic area

• Consider / account for in- and out- migration

Examples: Open/ dynamicpopulation

• Cancer incidence among never-married men aged 15-54 yrs and resided in San Francisco – Period of FU 1973-1990– Changeable characteristics- marriage, age, place

of residence – FU of 1,930,000 person years – incidence of NHL increased by 20 times, but rectal

cancer remained same

Fixed population

• Membership criteria is irrevocable / fixed – Giving birth to a baby – Undergoing a medical procedure – Eating contaminated food– Joining military – Presence during a disaster

• Exposures do not change over time • Followed for a fixed period• Loss of members may occur

Examples: Fixed population

• World war II- Hiroshima & Nagasaki nuclear bombing – Biological effects of radiation exposure – Monitoring of mortality and cancer incidence

among 94000 residents who were in the city and 27000 residents who were outside the city during bombing

– Follow up for disease incidence

Closed population

• Same as fixed cohort – Membership criteria is irrevocable / fixed

• Giving birth to a baby • Undergoing a medical procedure • Eating contaminated food• Joining military • Presence during a disaster

– Exposures do not change over time – Followed for a fixed period

• But NO Loss of members occur

Examples: Closed population

• To examine risk of GI infection during one week after an eating of certain type of food among people attending a party – Assuming the symptoms would start relatively fast and

will end by 7 days – Everybody who attended the party is a member – Follow up starts at the end of the party and continues

till one week– No loss of member, as period of observation is short – Estimate cumulative incidence

Exposure

• Event that has bearing on the outcome of interest

Cohort Study (Prospective Design)

Passive smoking & respiratory infections in children

• Is passive exposure to tobacco smoke associated with increased respiratory infections in children ?

• Design:Children exposed and not exposed tobacco

smoke in their homesFollow them in time for disease occurrence.

Children (<12 yrs)

1000

Family smoker500 childrenExposed

Family non-smoker500 childrenNot exposed

1 year

Diseased 300

Not diseased 200

Diseased 120

Not diseased 380

OutcomeStart

Rate: Incidence rate

•Incidence of Resp. Infection among exposed children: 300

500 = 60%

•Incidence of Resp. Infect. Among non exposed children: 120

500 = 24%

Cohort Study (cont.)Relative Risk: Incidence rate among exposed Risk Ratio Incidence rate in non exposed.

60 24 = 2.5

Relative Risk is a direct measure of risk (to assess the etiologic role of a factor in disease occurrence).

300 x 500 500 120

Cohort Study (cont.)Relative Risk:Smoking- Lung Cancer mortality: RR=18.57- Myocardial infarction mortality: RR=1.35

It measures the strength of association

Cohort Study (cont.)Attributable Risk: The absolute difference in

Incidence rates among groups. “Risk Difference” RD

60 - 24 = 36%The extent to which the incidence of disease can

be attributed to the risk factor

Smoking-Lung cancer mortality: RD=1.23-Myocardial infarction mortality RD=1.25

Annual Death Rates / 100,000 persons Exposure Category

Lung Cancer Coronary Heart D. 166 599

7 422

166 / 7 = 23.7 599 / 422 = 1.4

166 – 7 =159 599 – 422 = 177

Heavy smokersNonsmokers

Measures of Excess Risk

Relative Risk:

Attributable risk:

Doll and Hill study : Mortality of British doctors cited from Mausner, 1985

• The previous table suggests that prevention of coronary heart disease would require alteration of other factors in addition to smoking.

• The population attributable risk: relates both relative risk and frequency of the factor in the population

• i.e. a large proportion of the deaths from lung cancer in the total population are due to smoking not only because of the high RR associated with smoking, but also bec large proportion of the pop that smoke.

Examples from the literature

• Framingham Heart Study initiated in 1948 by US Public Health Services:

to study the relationship of a variety of factors to the subsequent development of heart disease

Group of persons30 – 62yrs

6,500Both sexes

20 years follow up

Information:S. cholest.levelBl.pressure , weightCig. Smoking

outcome

Occupation Based Studies to study effect of exposures

•

•Benzene workers and Leukemia• Coke-oven workers and lung cancer•Asbestos workers and lung cancer•Radium dial painters and oral cancer

Males Females(45-54y) (45-54)

Initial Serum Cholesterol Level

RR RR1.35 1.31.48 1.432.85 2.573.25 2.89

200 - < 220220 - < 240320 - < 340340 - < 970

There is an increasing risk of CHD with increasing initialSerum cholest. Levels in the 45-54 age group from a relativeRisk of 1.13-3.25 M, 1.13-2.89 F

1/9/2007 Cohort studies 77

Relating risk factors to health outcomes – questions

• Is this health condition associated with this exposure?– Association not = causation but may reflect it

• How strongly are these two factors related?– Strong association more likely causal

• How much of a disease can be attributed to a causative factor?


What is an association?

Factors are associated if:• the distribution of one factor is

different for different values of another.

• knowing the value of one factor gives information about the distribution of the other.

9/20/2000 79

Example – oral contraceptives and CHD

OC No OC Total

CHD 30 20 50

No CHD 30 70 100

Total 60 90 150

9/27/2004 80

Example – oral contraceptives and CHD (positive association)

OC No OC Total

CHD 30 20 50

No CHD 30 70 100

Total 60 90 15030% (30/100) of controls OC, overall

60% (30/50) of CHD

cases used OC

9/27/2000 81

Example – oral contraceptives and breast cancer

OC No OC Total

Cancer 15 35 50

No cancer 30 70 100

Total 45 105 150

9/27/2004 82

Example – oral contraceptives and breast cancer (no association)

OC No OC Total

Cancer 15 35 50

No cancer 30 70 100

Total 45 105 15030% (30/100) of noncases used OC

30% (15/50) of cases used

OC


Measures of association

• Can compare incidences (rate or proportion), prevalences

• Look at differences (e.g., “incidence difference”) (retains units)

• Look at ratios (e.g., “incidence ratio”) (no units)


Translating measures of association

If incidence ratio for runners / non-runners = 3.0:–“Incidence in runners was 3 times that in non-runners.”

–“Incidence in runners was 3 times as great as in non-runners.”

–“Incidence in runners was 200% greater than incidence in non-runners.” [(3.0 – 1.0) / 1.0 = 200%]



“Incidence in runners was 3 times greater than incidence in non-runners” is ambiguous

• Does it mean incidence ratio = 3.0 ?

• Does it mean incidence ratio = 4.0 ?



If incidence for runners / non-runners = 0.30:–“Incidence in runners was 0.30 times that in non-runners.”

–“Incidence in runners was 30% of that in non-runners.”

–“Incidence in runners was 70% lower [or “less”] than incidence in non-runners.” [(1.0 – 0.30) / 1.0 = 0.70 = 70%]



Or, can say “Incidence in non-runners was 3.3 times as great as incidence in runners”.


Measures of impactConcept of attributable risk

– How much of a disease can be attributed to a causative factor?

– What is the potential benefit from intervening to modify the factor?

Important for– Public health policy– Legal liability– Clinical/individual decisions


Example questions–Now that I am 35 years old, my CHD risk

from taking oral contraceptives is twice as great as when I was 25. But how much more risk do I have due to taking the pill?

–How much of the risk of heterosexual transmission of HIV might be eliminated through eliminating bacterial sexually transmitted diseases?


Example questions• How many cases of asthma are due to

ambient sulfur dioxide?• What proportion of motor vehicular deaths

can be prevented by mandatory seat belt use.

• What proportion of perinatal HIV transmission has been prevented through the use of prenatal, intrapartum, and neonatal zidovudine (AZT)?


Simplifying assumptions1. “Exposure” either causes or prevents the

outcome, but not both (no two-edged swords)

2. “Exposed” and “unexposed” groups are alike in all other respects (no confounding)

3. No other causes “compete” with the exposure


Several concepts

Concepts

• “Absolute” versus “relative”

• Exposed versus total population

• Disease caused, disease prevented


Many terms, many meanings

E.g., “attributable risk” can mean:

–Risk difference

–Population attributable risk percent

–Concept of assessing impact


“Absolute” perspectiveHow much risk?

– In exposed persons: risk difference (I1– I0)

– In the total population: (I1– I0) x exposure prevalence (P1)

How many cases? (I1– I0) x # of exposed persons (n1)


Relative perspective

What proportion of the risk is attributable?(What proportion of cases could be eliminated?)

In exposed persons: (I1– I0) / I1 = (IR–1) / IR

(Relative strength of association)

In the population: (I – I0) / I

(Strength of association and prevalence)


How much risk? What %?How many cases? What %?

E E Total

D 40 20 60

D 960 1,980 2,940

Total 1,000 2,000 3,000

I1 =___ I0 =___ I =___


How much risk? What %?How many cases? What %?

E E Total

D 40 20 60

D 960 1,980 2,940

Total 1,000 2,000 3,000

I1 =0.04 I0 =0.01 I =0.02


Attributable risk diagram

I1 I1 I1 – I0 =

"AttributableI0

I0 n0 I0 n1I0 risk"

n0 n1 p1= n1/n

Attributable cases


Prevented fraction diagram

I0 I0

I1I0 n0 I0 n1

I1

n0 n1 p1= n1/n

Prevented cases

Advantages of Cohort Study

• Correct classification of exposure before disease develops.

• Permits calculation of incidence rates thus, a direct measure of relative risk, and attributable risk.

• Many possible outcomes to the same exposure can be studied.

• No chick egg dilema• Accurate

Disadvantages of Cohort Study

• Large number of people are needed (large scale).• Time consuming (follow up)• Losing people in follow up (Attrition)• Expensive• Status of subjects may be changed leading to

error in classification of exposure eg. Change in habit, occupation.

• Administrative problems: loss of staff, funding, high costs of the extensive record keeping

Non concurrent studies Retrospective Cohort

• The period of observation starts from some date in the past.

• They usually involve specially exposed groups or industrial populations.

• Done by using company records of past & present employees:

• Information: - date of employment - date of departure - duration, degree of

exposure - status: living/dead

Nested case control studies

epidemiological studies. experimental studies scientifically rigorous considered as natural...

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