EP711

COHORT STUDIES

Types of Epidemiologic Studies

• Observational

Cohort

Case-control

•ExperimentalRandomized controlled trials

Definition: A study in which two or more groups of people that are free of

disease and that differ according to the extent of exposure

(e.g. exposed and unexposed) are compared with respect to

disease incidence

Cohort studies are the observational equivalent of experimental studies

but

The researcher cannot allocate exposure –he/she must locate a natural experiment to observe the relationship

between the exposure and disease

Cohort StudiesCohort Studies

ComparisonComparison

Active Intervention

Active Intervention

Outcome?

Randomized Controlled TrialsRandomized Controlled Trials

Exposed

Unexposed

Identify the study

population (cohort)

Design:

• Investigator randomly assigns exposure (treatment)

• Then observe over time for subsequent outcome

Design:

• Non-diseased subjects grouped based on presence of exposure

• Then determine subsequent outcome (e.g.- disease)

Example: Is smoking associated with lung cancer?

Non-smokersNon-smokers

SmokersSmokers

Outcome?

Cohort StudiesCohort Studies

Exposed

Unexposed

Identify the cohort

Advantages of Cohort StudiesAdvantages of Cohort Studies

• Temporal sequence between exposure & disease is clear (e.g., smoking preceded cancer)

• Can directly calculate incidence, RD, PRD

• Good for looking at rare exposures or unusual risk factors (e.g. agent orange)

• Can evaluate multiple effects of a single factor

Start of Study

Start of Study

PastPast FutureFuture

Compare Incidence

Have factor

Don’t have factorThe Cohort

Retrospective Cohort StudyRetrospective Cohort Study

•Cheaper, faster•Efficient with diseases with long latent period•Exposure data may be inadequate (limitation)

Start of Study

Start of Study

PastPast FutureFuture

Compare Incidence

Have factor

Don’t have factorThe

Cohort

Prospective Cohort StudyProspective Cohort Study

•More expensive, time consuming•Not efficient for diseases with long latent periods •Better exposure and confounder data•Less vulnerable to bias

Prospective partRetrospective part

Past Future

CompareIncidence

CompareIncidence

Start of Study

Ambidirectional Cohort StudyAmbidirectional Cohort Study

Contains elements of both types of studies

Have factor

Don’t have factor

Types of Cohort Populations

Types of Cohort Populations

• Open or Dynamic

– Changeable characteristic– Members come and go– Losses may occur

• Fixed– Irrevocable event– Does not add new members– Losses may occur

• Closed– Irrevocable event– Does not add new members – No losses occur

Never marriedResidents of Boston

Aged 25-54

Baby Boomers, 9/11 survivors,RCT participants

Church Picnic or Wedding Attendees

Choice depends upon hypothesis under study and feasibility considerations

• For common risk factors(obesity, HBP): A cohort from the general population (e.g., Framingham Heart Study, NHANES)

A special study group, e.g., doctors or nurses (e.g. The Nurse’s Health Study, Black Women’s

Health Study)

• For unusual risk factors : A special (rare) exposure group:

(e.g., Agent Orange, Hiroshima, Occupational)

Selection of Study PopulationSelection of Study Population

The Framingham Heart Study

• Initiated by NHLBI

• Objective was to identify the common factors or characteristics that contribute to CVD by following healthy individuals

• The researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts

• Since 1948, the subjects have continued to return to the study every two years for a detailed medical history, physical examination, and laboratory tests

• In 1971, the study enrolled a second generation - the original participants' adult children and their spouses

• In April 2002 the Study entered a new phase: the enrollment of a third generation of participants, the grandchildren of the original cohort.

The Nurse’s Health Study

• 2 cohorts; Differ by age

• NHS I–Assembled in 1976–~122,000 female nurses aged 30-55 years

• NHS II–Assembled in 1989–117,000 female nurses aged 25-42 years

• Biennial postal questionnaires

The Nurse’s Health StudyThe Nurse’s Health Study

• The primary goal to investigate the potential long term consequences of the use of oral contraceptives, in a population of normal women

• Primary outcomes include heart disease & cancer (common endpoints)

• Examines multiple common risk factors (diet, exercise, obesity, vitamin use)

• Subjects able to respond with a high degree of accuracy

• Motivated to participate in a long term study

• Easy to locate

• The U.S. military sprayed some 11 million gallons of the defoliant over southern and central Vietnam from 1962 to 1971 in an effort to expose enemy supply lines, sanctuaries and bases.

• Airmen were exposed during spraying flights, while loading the chemical and while performing maintenance on the aircraft and the spraying equipment.

• Agent Orange was named for the orange-striped barrels it was shipped in. It contains dioxin, a cancer-causing byproduct linked to medical ailments in U.S. war veterans and their Vietnamese counterparts.

Air Force Ranch Hand Study

(“Agent Orange Study”)

1) As similar as possible with respect to other factors that could influence outcome

2) Comparable & accurate information

Counterfactual ideal

• The ideal comparison group consists of exactly the same individuals in the exposed group – but without the exposure

• Epidemiologists must select different sets of people who are as similar as possible

Selection of the Comparison Group Selection of the Comparison Group

Exposed Unexposed

General PopulationGeneral PopulationGeneral Population

Internal Comparison Comparison CohortGeneral Population

Comparison

vs.

Land-scapers/Grounds

Crew

Road Crew/

AsphaltWorkers

GeneralPopulation

RubberWorkers

vs.Lean Obese

vs.

Nurses

Sources of Comparison GroupSources of Comparison Group

Which of the three comparison groups is best?

“Healthy-Worker Effect”“Healthy-Worker Effect”

• Rates of morbidity and mortality among a working population are lower than those of the general population

• Health requirements for workers (especially physical laborers) tend to be stringent

• General population consists of both healthy and ill people

• Leads to underestimation of risk

Pre-Existing Records

Advantages•Inexpensive•Recorded before disease occurrence

Disadvantages•Inadequate level of detail•Missing records•Little or no information on confounders

Sources of Exposure Information

Sources of Exposure Information

Questionnaires, Interviews

Advantages•Good for information not routinely recorded

Disadvantages•Potential for recall bias

Sources of Exposure Information

Sources of Exposure Information

Direct Testing

(Physical exams, tests, environmental monitoring)

Advantages•Good for certain exposures

Disadvantages•Expensive•Not feasible in large studies

Sources of Exposure Information

Sources of Exposure Information

• Death certificates• Physician, hospital, health plan records• Questionnaires (verify by records)• Medical exams

Sources of Outcome Information

Sources of Outcome Information

You can use blinding to ensure that there is comparable ascertainment of the outcomes in both groups

Goal is to obtain complete follow-up information on all subjects regardless of exposure status

• Ascertainment of outcome data involves following all subjects from exposure into the future

• Time consuming process

• However, high losses to follow-up raise doubts about the validity of the study (bias)

Follow-upFollow-up

If likelihood of loss to follow up is related to the risk factor and the outcome, the estimate of the association will be biased

Loss to Follow Up

Example:True incidence of thromboembolism:

Subjects lost to follow up: 1,012 1,008

Subjects with TE lost to follow up:

Apparent incidence of TE:

OC Users Non-OC users

20/10,000 10/10,000

12 2

8/8,988 8/8,992

True RR = 2.0 Apparent RR = 1.0

Can occur in prospective cohort studies and in experimental studies

Effects: can produce over- or under- estimate of association.

•Town lists•Telephone books, 411•Vital records (birth, death, marriage)•Registry of Motor Vehicles (RMV) lists•MD & Hospital records•Internet•Credit bureau•Relatives, friends (“contacts”)•Professional registries (AMA, RN, ABA, etc.)

Follow-up ResourcesFollow-up Resources

Tuberculosis Treatment and Breast Cancer Study

Tuberculosis Treatment and Breast Cancer Study

Follow-up Strategies

Begin with an interested group Collect identifiable information

Full name & AddressDOB, SSNContact information

Maintain frequent contact with all respondents Regular mail (questionnaires, newsletters)Telephone callsPersonal contact (if possible)

Incentives (gifts, calendars, money)

Analysis of Cohort Study Analysis of Cohort Study

• Basic analysis involves calculation of incidence of disease among exposed and unexposed groups

• Depending on available data, you can calculate cumulative incidence (CI) or incidence rates (IR)

• Recall set up of 2 x 2 tables

Person-Time In A Prospective Cohort Study

Person-Time In A Prospective Cohort Study

SubjectA-B-C-D-E-F-G-H-I-J-K-L-

x

x

xP1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13

Total time at risk =107.7 Total person-yrs

Timeat Risk

8.311.0

14.014.0

10.2 3.0

7.0

10.0

3.0

9.06.2

12.0

x= when theygot disease

D

?

D

?

X= when they got diseaseD= death? = Lost to follow-up

Analysis of a Cohort Study

CasesPerson-Years of follow-up

Exposed A PYE

Unexposed C PYU

Total A+C PYE + PYU

IRE = A/PYE IRU = C/PYU

RR = IRE/IRU

Interpretation: The RR is the risk of developing the outcome in the exposedrelative to the unexposed

Start of Study

Future

Examine the associationBetween obesity and CHDIn a sample of 117,000 RNs w/o cardiovascular disease

Compare Incidence of Disease

obese

lean

Nurse’s Health StudyNurse’s Health Study

Have risk factor

Don’t have it

Follow-up Surveys

AnalysisAnalysis

CHD Cases

Woman-Years of follow-up

Obese (Exposed)

85 99,573

Lean (Unexposed)

41 177,356

Total 126 276,929

IR1 = 85/99,573 = 8.54/10,000 woman-years

IR0 = 41/177,356 = 2.31/10,000 woman-years

RR = IR1/IR0 = 3.7

Obese women had 3.7 times the risk of CHD compared to lean women

Obesity Rate of CHD ?

<21

21-<23

23-<25

25-<29

>29

BMI: CHD cases

41

57

56

67

85

Person-yearsof observation

177,356

194,243

155,717

148,541

99,573

Rate of CHD per100,000 P-Yrs

(incidence)

29.3

36.0

45.1

Risk Ratio

1.0

3.7

Risk Ratio In The Nurses Risk Ratio In The Nurses Health StudyHealth Study

Risk Ratio In The Nurses Risk Ratio In The Nurses Health StudyHealth Study

23.1

85.4

Risk Ratio = 85.4/100,000 / 23.1/100,000 = 3.7

Obesity Rate of CHD ?

CHDcases

41

57

56

67

85

person-yearsof observation

177,356

194,243

155,717

148,541

99,573

rate of CHD per100,000 P-Yrs

(incidence)

23.1

29.3

36.0

45.1

85.4

Risk Difference

0.0

62.3

Risk Difference = 85.4/100,000 - 23.1/100,000 = 62.3 excess cases per 100,000 P-Yrs in heaviest group

Risk Difference In The Risk Difference In The Nurses Health StudyNurses Health Study

Risk Difference In The Risk Difference In The Nurses Health StudyNurses Health Study

<21

21-<23

23-<25

25-<29

>29

BMI:

Strengths of Cohort StudiesStrengths of Cohort StudiesStrengths of Cohort StudiesStrengths of Cohort Studies

• Efficient for rare exposures

• Usually good information on exposures

• Can evaluate multiple effects of an exposure

239 3

139

Yes No

Orthopedic Problems

98

119

Yes No

Breast Cancer

138

169

Yes No

Cardiovascular Disease

227 320,807

217 310,820

Yes P-Yrs

Reproductive ProblemsYes

No

Obesity

A Cohort Study Can Look at Multiple Outcomes

A Cohort Study Can Look at Multiple Outcomes

Disadvantages to Cohort Studies(especially prospective)

Disadvantages to Cohort Studies(especially prospective)

• May need large numbers of subjects for long periods of time

• Can be expensive and time consuming

• Not good for rare diseases or those with long latency

• Loss to follow up undermines validity

• How were the study groups selected or defined?

• Did they differ in other ways that could influence the outcome?

• Were the data accurate? • Was data collection comparable for all study groups?

• How complete was the follow-up?

When Reading A Cohort Study, Ask…

When Reading A Cohort Study, Ask…

The Black Women’s The Black Women’s Health Study (BWHS)Health Study (BWHS)

A Follow-up Study of

African-American Women

Boston University

Slone Epidemiology Center

Why Is The BWHS Needed?Why Is The BWHS Needed?

• Rates of illness and death from many diseases are higher in African-American women

• Lack of health research studies involving African-American women, particularly large studies

156

95

4023

133109

Heart Stroke Cancer

Death rate per 100,000 women

BlackWhite

Exposure and Outcome Information

• Biennial postal questionnaires

• Self-report

1995 Questionnaire Data:Baseline

• Age• Weight• Height• Waist, hip circumference• Use of medical care• Occupation• Education• Medical history (prevalent disease)• Reproductive history• Drugs (OCs, HRT, vitamins, medications)• Cigarette smoking• Alcohol use• Diet (60 item Block-NCI questionnaire)• Physical activity• Family care responsibilities

1997-2007 Follow-up Questionnaires1997-2007 Follow-up Questionnaires

Update “exposures” for previous 2-year period:(e.g., OC use, weight, alcohol use, cigarette smoking, physical activity, etc.)

Record “outcomes” for previous 2-year period:Incident disease, Births, Deaths

Additional questions:Ancestry (race, ethnicity, where born) Lupus symptom list Experiences and perceptions of racism Hair straightener useFamily history of disease Exposure to violence Use of herbal remedies Individual health/belief systemDepression scale (CESD)* Household Income Education * Diet *Religion/Spirituality Perceived stress and copingDental health Access to car/transportationSiblings/birth order

*Repeat Question

1995 – 2007 Questionnaire Data1995 – 2007 Questionnaire Data

Prevalent and incident diseases and conditions:

Hypertension Cervical cancerDiabetes Rheumatoid arthritisHigh cholesterol OsteoarthritisHeart attack GingivitisAngina DepressionStroke SarcoidosisClot in lung, leg AsthmaCyst in breast Toxemia/Pre-eclampsiaFibroids Gastric/duodenal ulcerEndometriosis Hydatidiform moleLupus Polycystic ovarySickle cell anemia GlaucomaBreast cancer Multiple SclerosisLung cancer Kidney StonesColon/rectal cancer Other - specify

ValidationValidation

• Self-reported data

• Important for minimizing bias (misclassification)

• Must confirm: Exposures (when feasible) Vital status (deaths) Outcomes

• Expensive, not feasible in most cohort studies

• Not all exposures can be easily validated (subjective measures)

• Perceptions and experiences of racism/unfair treatment

• Can be accomplished in a sample of the cohort

• Anthropometric (height, weight, hip & waist circumference)

• Physical Activity

• Diet

Validation: ExposuresValidation: Exposures

Diet Validation StudyDiet Validation Study

• 408 BWHS Participants

• Over a 1-year period (quarterly) provided:

• 3 telephone 24 hour diet recalls

• 1 3-day food diary

• Compared nutrient intake estimates

• FFQ Data vs. Combined recall & diary data

Kumanyika et al., Ann Epidemiol 2003;13:111-118

Validation: OutcomesValidation: Outcomes

Non-medical cohort:

• Symptoms of illness are nonspecific

• Participants may not know the diagnosis even if it was made

• Direct examinations not feasible in a large cohort study

Validation: OutcomesValidation: Outcomes

Information requested depends on outcome studied

– Breast cancer and other cancers: hospital records, pathology reports, discharge summaries, CA registry data

– Coronary heart disease: hospital records, discharge summaries

– Lupus, RA, MS, Sarcoidosis: hospital records, physician checklists

– Hypertension and Diabetes: self-report plus use of appropriate drug, physician checklists

Challenges Challenges

Medical records

Difficulties in obtaining records

• Additional consent process (medical release)

• Incomplete records

• Records from multiple sources

• Physician checklists: a burden on physician

»Remedies

• Patient checklists

• Registry Data (Cancer)

Validation: Deaths

• Important for follow-up (person-time and outcome)

• Reported by: » Next of kin» Post office» Internet» SSDMF» NDI

• Confirmed by: » Death Certificate with date and cause(s) of death

• Supplied by:» State registrar» Next of kin

Challenges

Obtaining death certificates

–State IRB process (varies by city and state)–State registry budget cuts–Takes time to receive certificates–Cost ranges from $0.37 to $20 per

certificate search

Remedy: − NDI plus− Gives DOD and coded cause of death− Still requires state IRB approval

Study ResultsStudy Results

• ~100 publications (manuscripts and abstracts)

• Full list available at:

www.bu.edu/bwhs/publications

Genomic StudiesGenomic Studies

• Collection of cheek samples (for extraction of DNA) from all BWHS participants between January 2004 and December 2007

• Samples sent to National Human Genome Center at Howard University

BWHS Genomic StudiesBWHS Genomic Studies

• Participants receive $15 AFTER their consent and sample have been received

• Samples stored at Howard University Human Genome Center for future analyses

• 56% (n~27,000) participation / ~5% refusal

• Non-responders followed-up via telephone calls

>>1 Move Between 1995-19971 Move Between 1995-1997

Age: <30 70%

30-39 57%

40-49 45%

50-69 39%

Russell, et al. AJE. 2001;154:845-53