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Cohort studies Case control studies Field methods


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Title: Cohort studies Case control studies Field methods

Cohort studiesCase control studiesField methods
  • Every epidemiological study should be viewed as a
    measurement exercise
  • Kenneth J. Rothman, 2002

What does this mean?
Cohort study
  • What is a cohort study?
  • Types of cohorts
  • Observational - retro, prospective,
  • Clinical trials
  • Other?
  • What is a fixed cohort? An open cohort?
  • What is the denominator in a cohort study?
  • How is it calculated?

Elements of longitudinal study designsEssential
question what is the nature of time?
Changes in exposures
Exposures At start of study
History of exposures
Exposures times
Study times
Study times
Longitudinal studies are all about change over
  • Change in level and effects of risk factors due
  • Physiological changes related (perhaps) to age
  • Selective survival
  • Differential due to higher mortality in high risk
  • Competing risk from other outcomes (esp death)
  • Differential attrition by exposure
  • Biasing effects of attrition
  • Time trends in population levels of exposure
  • Reverse causality of disease on exposure
  • Proximity of exposure measurement to outcome

Factors determining trends with age in risk
factordisease associations
Change over time in risk-factor disease
Classifying person time exposed
What is the consequence for effect estimates of
misclassifying exposure time?
Estimating exposure over time
  • Measurement of exposure (validity, reliability)
  • Change over time in exposure
  • Baseline
  • After baseline
  • Time that is unexposed
  • baseline time, average over time, cumulative

Time exposed vs. time at risk
  • Time from exposure to event
  • Induction period
  • Threshold of cumulative exposure
  • Average exposure, cumulative exposure,
  • Immortal person time (?)
  • Reverse causality

Example of cohort study
The 32-year relationship between cholesterol and
dementia from midlife to late life
Background Cellular and animal studies suggest
that hypercholesterolemia contributes to
Alzheimer disease (AD). However, the relationship
between cholesterol and dementia at the
population level is less clear and may vary over
the lifespan. Methods The Prospective
Population Study of Women, consisting of 1,462
women without dementia aged 3860 years, was
initiated in 19681969 in Gothenburg, Sweden.
Follow-ups were conducted in 19741975,
19801981, 19921993, and 20002001. All-cause
dementia was diagnosed according to DSM-III-R
criteria and AD according to National Institute
of Neurological and Communicative Disorders and
StrokeAlzheimers Disease and Related Disorders
Association criteria. Cox proportional hazards
regression examined baseline, time-dependent, and
change in cholesterol levels in relation to
incident dementia and AD among all participants.
Analyses were repeated among participants who
survived to the age of 70 years or older and
participated in the 20002001 examination. Result
s Higher cholesterol level in 1968 was not
associated with an increased risk of AD (highest
vs lowest quartile hazard ratio HR 2.82, 95
confidence interval CI 0.948.43) among those
who survived to and participated in the 20002001
examination. While there was no association
between cholesterol level and dementia when
considering all participants over 32 years, a
time dependent decrease in cholesterol over the
follow-up was associated with an increased risk
of dementia (HR 2.35, 95 CI 1.224.58). Conclusi
on These data suggest that midlife cholesterol
level is not associated with an increased risk of
AD. However, there may be a slight risk among
those surviving to an age at risk for dementia.
Declining cholesterol levels from midlife to late
life may better predict AD risk than levels
obtained at one time point prior to dementia
onset. Analytic strategies examining this and
other risk factors across the lifespan may affect
interpretation of results. Mielke et al in
Neurology 20107518881895
Attrition, cumulative mortality, cumulative
person years
Fig 1 - Mean cholesterol levels in the
Prospective Population Study of Women by
examination year andbirth cohort
Table 1 Characteristics of PPSW participants by
dementia status over 32years (n 1,462)
A9R7A98 MIELKE tab 2.xlsx
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Case-Control Studies
General Definition of a Case-Control Study A
method of sampling a population in which cases of
disease are identified and enrolled, and a sample
of non-cases of the population that produced the
cases is identified and enrolled. Exposures are
determined in the same way for individuals in
each group.
  • This disparaging term was given to case-control
    studies because their logic seemed backwards and
    they seemed more prone to bias than other
  • No basis for this derogation.
  • Case-control studies are a logical extension of
    cohort studies and an efficient way to learn
    about associations.

  • Hypo. Example Vitamin D exposure increases the
    risk of breast cancer.
  • Consider a hypothetical prospective cohort study
    of 89,949 women aged 34-59 1,439 breast cancer
    cases identified over 8 years of follow-up
  • Blood drawn on all at beginning of follow-up and
  • Exposure Level of Vit D in blood characterized
    as high or low

  • Results

Breast Cancer
Vit D
  • Practical Problem Quantifying Vit D levels in
    the blood is very expensive -- it's not practical
    to analyze all 89,949 blood samples
  • To be efficient, analyze blood on all cases
    (N1,439) but just take a sample of the women who
    did not get breast cancer, say two times as many
    cases (N2,878)

All cases and subsample of controls
Breast Cancer
Vit D
These data can be used to estimate the relative
  • Identify cases of disease from a defined
  • take a sample of controls from that population.

When is it a good idea to conduct a case-control
  • When exposure data are expensive or difficult to
  • - Ex Vit D study described earlier
  • When disease has long induction and latent period
  • - Ex Cancer, cardiovascular disease
  • When the disease is rare
  • Ex Studying risk factors for birth defects
  • When little is known about the disease
  • Ex. Early studies of AIDS
  • When underlying population is dynamic
  • Ex Studying breast cancer on Cape Cod

  • Criteria for case definition should lead to
    accurate classification of disease
  • Efficient and accurate sources should be used to
    identify cases eg, existing registries,

Cases give you the numerators of the rates of
disease in exposed and unexposed groups being
  • Rate of disease in exposed a/?
  • Rate of disease in unexposed c/?

The denominators are missing. If this were a
cohort study, you would have the total population
(if you were calculating cumulative incidence) or
total person-years (if you were calculating
incidence rates) for both the exposed and non
exposed groups, which would provide the
denominators for the compared rates.
Where do you get the information for the
denominators in a case control study? THE
  • A case-control study can be considered a less
    costly, more efficient form of a cohort study.
  • Cases are the same as those that would be
    included in a cohort study.
  • Controls provide a fast and inexpensive means of
    obtaining the exposure experience in the
    population that gave rise to the cases.

  • Definition A subsample of the source population
    that gave rise to the cases.
  • Ideal nested case-control study from a cohort
  • Purpose To compare the exposure distribution in
    the source population that produced the cases.

Selecting Controls
  • General population controls
  • Existing cohort study
  • Most often used when cases are selected from a
    defined geographic population
  • Sources random digit dialing, residence lists,
    drivers license records

Selecting Controls
  • Advantages of general population or cohort study
  • Because of selection process, investigator is
    usually assured that they come from the same base
    population as the cases.
  • In a cohort, exposure is standardized for both
    cases and controls

Selecting Controls
  • Disadvantages of general population controls
  • Time consuming, expensive, hard to contact and
    get cooperation may remember exposures
    differently than cases (recall bias)

Selecting Controls
  • Hospital controls
  • Used most often when cases are selected from a
    hospital population

Example Study of cigarette smoking and
myocardial infarction among women. Cases
identified from admissions to hospital coronary
care units. Controls drawn from surgical,
orthopedic, and medical unit of same hospital.
Controls included patients with musculoskeletal
and abdominal disease, trauma, and other
non-coronary conditions.
  • Advantages of hospital controls
  • Same selection factors that led cases to hospital
    led controls to hospital (?)
  • Easily identifiable and accessible (so less
    expensive than population-based controls)
  • Accuracy of exposure recall comparable to that of
    cases since controls are also sick (?)
  • More willing to participate than population-based

  • Disadvantages of hospital controls
  • Since hospital based controls are ill, they are
    unlikely to accurately represent the exposure
    history in the population that produced the cases
  • Hospital catchment areas may be different for
    different diseases

  • What illnesses make good hospital controls?
  • Those illnesses that have no relation to the
    risk factor(s) under study
  • Q Should respiratory diseases be used as
    controls for a study of smoking and myocardial
    infarction? Do they represent the distribution of
    smoking in the entire population that gave rise
    to the cases of MI?

Selecting Controls
  • Special control groups like friends, spouses,
    siblings, and deceased individuals.
  • These special controls are rarely used.
  • Exposures in these controls may not be
    independent of cases, eg, diet in families. What
    effect would that have on the estimate?
  • Some cases are not able to nominate controls
    because they have few appropriate friends, are
    widowed, or are only or adopted children.
  • Dead controls are tricky to use because they are
    more likely than living controls to smoke and

Sampling a cohort population for controls nested
case-control study
  • 1. Sample the population at risk at the start of
    the observation period
  • -------------------------------------------------
  • Start FU
    End FU

Sampling a cohort population for controls nested
case-control study
  • 2. Sample population at risk as cases develop
  • -------------------------------------------------
  • Start FU
    End FU

Sampling a cohort population for controls nested
case-control study
  • 3. Sample survivors at the end of the observation
  • -------------------------------------------------
  • Start FU
    End FU

Nested case-control study on Vit D and breast
  • Hypothetical cohort study of 89,949 women 1,439
    breast cancer cases identified over 8 years of
  • Blood drawn on all 89,949 at beginning of
    follow-up and frozen
  • Exposure Level of Vit D in blood characterized
    as high or low

Nested case-control study on Vit D and breast
Breast Cancer
Vit D
Analyzed blood on all cases (N1,439) and a
sample of controls (N2,878 3.3 of non cases).
Analysis of case-control studies
Because controls are a sample of the population
that produced the cases, size of the total
population may be unknown.
Analysis of case-control studies
  • Two possible outcomes for an exposed person case
    or not
  • Oddsa/b
  • Two possible outcomes for an unexposed person
    case or not Oddsc/d
  • Odds ratio odds of an exposed person being a
    case a/b ad/bc
  • odds of unexposed person being a case c/d
  • Just like the incidence rate ratio and cumulative
    incidence ratio, the odds ratio is a ratio
    measure of association.

Analysis of case-control studies
  • EXAMPLE Case control study of spontaneous
    abortion and prior induced abortion (OUTCOME
    spontaneous abortion EXPOSURE prior induced

Analysis of case-control studies
  • Odds of being a case among the exposed
  • 42/247 (a/b)
  • Odds of being a case among the unexposed
    107/825 (c/d)
  • Odds ratio (a/b) / (c/d)
  • (42/247) / (107/825)
  • Women with a history of induced abortion had a
    30 increased risk of having a spontaneous
    abortion compared to women who never had an
    induced abortion.

Strengths of case-control studies
  • Efficient for rare diseases and diseases with
    long induction and latent period.
  • Can evaluate many risk factors for the same
    disease. So, good for diseases about which little
    is known.

Weaknesses of case-control studies
  • Inefficient for rare exposures
  • Vulnerable to bias because of retrospective
    nature of study
  • May have poor information on exposure because
  • Difficult to infer temporal relationship between
    exposure and disease
  • How do these strengths and weaknesses
    compare to cohort studies?

SUMMARYIs a Cohort an imitation of a randomized
controlled trial?
  • Gold-standard (?) randomized, placebo-controlled,
    double-blinded study
  • Least biased ?
  • Exposure randomly allocated to subjects -
    minimizes selection bias
  • Masking of exposure status in subjects and study
    staff minimizes information bias
  • Selection bias into trials
  • Generalizability of trial is not usually good
  • Trials often suffer from the same biases as
    observational studies

Bias in prospective cohort studies
  • Loss to follow up
  • The major source of bias in cohort studies
  • Assume that all do / do not develop outcome?
  • Ascertainment and interviewer bias
  • Some concern Knowing exposure may influence how
    outcome determined
  • Non-response, refusals
  • Little concern Bias arises only if related to
    both exposure and outcome
  • Recall bias
  • No problem Exposure determined at time of

Bias in retrospective cohort case-control
  • Ascertainment bias, participation bias,
    interviewer bias
  • Exposure and disease have already occurred ?
    differential selection / interviewing of
    compared groups possible
  • Recall bias
  • Cases (or ill) may remember exposures differently
    than controls (or healthy)

  • Field methods in epidemiology

Getting keeping participants
  • Target population
  • Study population
  • Intervention vs. observational cohorts
  • Sources of information on eligible participants
  • Human subjects
  • Eligibility screening
  • Retention
  • Recruitment
  • http//
  • Incentives
  • Participant burden
  • Selection bias
  • Attrition bias

Would you join the National Childrens study?
Sacramento Area Latino Study on Aging (SALSA)
Location of study population
SALSA Study Counties Census Tracts Percent
Sacramento City
Data Source U.S. Census Bureau, 2000 Census of
Population and Housing, Summary File 3 Technical
Documentation, 2002.
SALSA Study Participants
Data Source U.S. Census Bureau, Geography
Division, Cartographic
Products Management Branch
Sacramento Area Latino Study on Aging Cohort
  • Study Population
  • 1,789 Latinos aged 60, primarily Mexican
    ancestry (95)
  • 49 US born and 51 Mexico or another Latin
    American country
  • 58.3 female
  • Mean age at baseline 71 (60-101)
  • 51 Spanish speaking
  • Median education 12 years in US born, 4 years in
  • Study period
  • Baseline 1998-99
  • Annual follow-up through 2008
  • Semi annual phone interviews
  • In home clinical evaluations and interview
  • Cognitive testing, clinical assessments
  • Socio-demographic factors
  • Medical history
  • Measured Vascular risk factors (blood pressure,
    obesity, diabetes)
  • Biological samples (DNA, blood, cortisol)
  • Mortality
  • Dementia

Sacramento Area Latino Study on Aging (SALSA)
Cohort Study, Baseline and Follow up 1998-2008
12-15 month Home Visits
Fasting blood draw in home visits
Semi-Annual phone calls
Neuropsychological Test , MRIs, and Diagnosis of
Mortality Surveillance- ongoing
Getting keeping high quality data
  • Method in person, phone, mail
  • Interview/questionnaire
  • Clinical information
  • Biological information
  • Data collection protocols
  • Pre/pilot testing
  • Data management
  • Electronic
  • Data entry
  • Coding
  • Review/QC

Questionnaire design problems
  • Survey data appear precise and factual, but are
    actually complex estimates
  • Some possible threats to accuracy derived from
    the questionnaire
  • Questions not understood as intended
  • Dont adequately capture respondent experience
  • Pose an overly challenging response task
  • Problems may not be visible in the actual survey
  • How can we find these before data collection?

What, to you, is your abdomen?
In the last year, have you been bothered by pain
in the abdomen?
  • Seems to be straightforward
  • But suppose we ask
  • What, to you, is your abdomen?
  • What does it mean to be bothered by pain in the
  • What period of time are you thinking about here

In the last year, have you been bothered by pain
in the abdomen?
  • Possible revisions
  • Show shaded picture of abdomen
  • Drop bothered
  • Use In the past 12 months
  • in the past 12 months have you had..
  • Define pain level, location, persistence
  • Clear alternatives address these problems, with
    no apparent drawbacks

Cognitive stages involved in responding to survey
  • Comprehension Respondent interprets the
  • Retrieval Respondent searches memory for
    relevant information
  • Estimation/Judgment Respondent evaluates and/or
    estimates response
  • Response Respondent provides information in the
    format requested

Comprehension task
  • Do you use any assistive devices to help with
    mobility, communication, self care, accessing
    your workplace?
  • Yes
  • NoSource 1972/74 Social Security
    Administration Survey of Disabled and Non
    Disabled Adults

Comprehension Transcription
  • Thats a mouthful of questions. Assistive
  • Well, I guess we all could be classified. We
    use glasses. I guess glasses are assisted devices
    and so I guess almost everyone has to say yes to
    that and in my case I wear glasses and I also
    have hearing aids. Thats it. I dont use a cane
    or anything

I think a lot of people may have trouble with
that question though because its kind of stiff
and formal. Like if you would say assistive
devices such as and give some examples, maybe a
person might pick up on it a little bit because
right off , the first thing I think about is a
walker or cane or something but you are telling
about hearing, communication which includes
hearing and speaking, seeing, all of those are
communication devices. Anyhow.
Retrieval task
  • How old were you when this (high blood pressure)
    was first diagnosed?
  • Source US/Canada Joint Health Survey

Retrieval Transcription
  • Huh, shoot I was in my forties but I dont
    remember exactly when
  • Because you said that it was in 1996
  • Yeah, I remember this so good because I moved
    back here in 95 I know I was in my forties

Judgment task
  • Some people who have health conditions,
    impairments, or disabilities get help from other
    people in order to get around, lift or carry
    things, communicate, keep track of things, or
    remember things.
  • As a result of your compression fracture, or your
    hearing or your shoulder, do you require help
    from other people?
  • Yes
  • NoSource Disability Statistics Institute

Judgment Transcription
  • I hate to say require, but of course I did
    require it when that compression fracture
    happened first but now Im back doing everything
    myself and I do have the neighbors come in and I
    have my lawn mowed instead mowing it and I have
    my gardening done instead of doing it and so
    forth so I guess I required help

Response task
  • Does a physical condition or mental health
    problem reduce the amount or the kind of activity
    you can do at home?
  • Yes, sometimes
  • Yes, often
  • NoSource Canadian Cooperative Survey

Response Transcription
  • Hmm theres something I cant do so hmmm and
    theres things that I can but with difficulty or
    with aid hmm so actually I dont have an answer
    to that I guess I would be if I have one always I
    guess we fall in the always
  • You really would like an always category
  • Yes

Summary of field operations
  • Recruitment issues retention issues
  • Pre/pilot test all protocols
  • Establish standardized protocol that is monitored
    throughout the study for quality