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Introduction to cohort study 王齡誼 [email protected] 2019/4/12

Introduction to cohort studyhlm.tzuchi.com.tw/.../2019/20190412_cohort-study.pdf · A cohort study can provides.. • Incidence: the number of newly diagnosed cases of a disease

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Text of Introduction to cohort studyhlm.tzuchi.com.tw/.../2019/20190412_cohort-study.pdf · A cohort study...

  • Introduction to cohort study

    王齡誼[email protected]

    2019/4/12

  • Learning objectives

    • To know what is cohort

    • To know the characteristics of cohort study

    – Incidence

    – Person-year

    – Relative risk/risk ratio/rate ratio

    • To know what is the ideal comparison

    group

    • To know the bias in cohort study

    • Advantages & disadvantages

  • Idea

    (hypothesis)

    Study

    design

    Statistical

    Analysis

    Experimental design

    • Randomized controlled trial

    Non-experimental (observational) design

    •Cohort study (世代追蹤研究)•Case-cohort study

    •Nested case-control study

    •Case-control study (病例對照研究)•Case-crossover study

    •Case-time control study

    •Cross sectional study (橫斷性研究)

    資料收集

    From idea to research

  • Test the hypothesis

    Environmental exposure

    or host characteristics

    Disease or other health

    outcome

    1. An association is

    observed2. Is the observed

    association causal?

  • Population

    Not

    Exposed

    Exposed

    Randomly

    Allocated

    Population

    Not

    Exposed

    Exposed

    Self-

    Selection

    RCT vs. Cohort study

  • What is cohort?

    Cohort studies:

    marching towards outcomes

  • Cohort Study

    Follow up

    Exposed Not

    Exposed

    Disease No

    disease

    Disease No

    disease

    Defined population

    Self selection

    Retro.

    1992

    2018

    Prosp.

    2018

    2032

  • Exposure Outcome

    1. 有A暴露的人,未來得B疾病的發生率(incidence rate)或危險性 (risk)?2. 有A暴露的人,未來罹患B疾病的發生率(或危險性)是沒有A暴露的人的幾倍,也就是說,有A暴露的人相對於沒有A暴露的人,其相對危險性(relative risk)為何?

    HBsAg status PHC

  • The framingham study

    Exposed Not Exposed

    Disease No

    diseaseDisease No

    disease

    Defines population

    (a town in Massacusetts, 30~62 year-old)

    Self selection

    Prosp.

    1948

    Blood pressure, smoking, body

    weight, diabetes, exercise, etc.

    Coronary heart disease, stroke,

    congestive heart failure, peripheral

    arterial disease, etc.

  • Cohort Study

    Exposed

    people

    Develop

    DiseaseDo Not

    Develop

    Disease

    Non-Exposed

    people

    Develop

    DiseaseDo Not

    Develop

    Disease

    If exposure is associated with disease:

  • A cohort study can provides..

    • Incidence: the number of newly diagnosed cases of a disease.

    • Risk is the number of new cases of a disease divided by the

    number of persons at risk for the disease.

    • Incidence rate is the occurrence rate of new cases of a disease

    in defined population during a specific time period. (person time

    at risk)

    # of new eventspersons at risk at begining of study

    # of new eventsperson-time at risk

  • Person-years (人年)

    Subjects Time

    at risk

    A 8.3

    B 11.0

    C 14.0

    D 14.0

    E 10.2

    F 3.0

    G 12.0

    H 7.0

    I 10.0

    J 3.0

    K 9.0

    L 6.2

    81 95

    Loss to f/u

    disease developed

  • Incidence ratesubjects Timeat risk

    A 8.3

    B 11.0

    C 14.0

    D 14.0

    E 10.2

    F 3.0

    G 12.0

    H 7.0

    I 10.0

    J 3.0

    K 9.0

    L 6.2

    Total time at risk =107.7 person-yrs

    Incidence density (0~infinity) :

    = 3/107.7

    =0.028/person-yr

    = 28/1000 person-yr

    = 2.33/1000 person-month

    = 0.54/ 1000 person-weeks

    Unit depends on investigators, frequency of

    event.

    Cumulative incidence (risk) (0~1):

    = # of new disease/ initial population

    =3/12

  • Design of a cohort Study

    Disease

    developed

    Disease

    Not

    developed

    Total

    Person-yr

    At risk

    Total

    subjects

    Incidence

    rates of

    Disease

    Exposes a b T1 a+ba/(a+b) or

    a/T1

    Non-

    exposed c d T2 c+dc/(c+d) or

    c/T2

    Association measure in cohort study

    exp

    non-exp

    risk

    risk

    a

    a bRRc

    c d

    當每人追蹤時間相同:

    exp 1

    non-exp

    2

    I

    I

    a

    TRR

    c

    T

    當每個人追蹤時間不同:

    1

    2

    Rate difference:Iexp –Inon-expRisk difference: riskexp-risknon-exp

  • Interpretation RR of a Disease

    RR Interpretation of RR

    =1 Risk in exposed equal to risk in non-exposed (no association)

    >1 Risk in exposed greater than risk in non-exposed (possibly causal)

  • Incidence rate & person years

    BMI #

    MIs

    Person-years

    at risk

    Rate of MI per

    100,000 person-Yrs

    (incidence rate)

    Crude

    RR

    29 85 99,573 85.4 3.7

  • Type of cohort• Dynamic cohort (Open cohort)

    – Exposure status may change during follow up

    – Subjects may enter the study at any time

    – The cohort is defined by person-times rather

    than on persons.

    • Fixed cohort

    – No new subjects enter the study after study

    follow-up date

    – Exposure status is consistent

    – If there is no loss to follow-up: closed cohort

  • CHOICE OF STUDY POPULATION

  • CHOICE OF COMPARISON GROUP

    Internal and external

  • The ideal comparison group

    臨床角度問問題: Do patients who receive an atypical antipsychotic drug have an increased risk of hip fracture?

    Cohort study角度問問題: What would have happened to these patients if they had not received the atypical

    antipsychotic drug?

    Ideally, the comparison group in the cohort study

    should be identical to the intervention group, apart

    from the fact that they did not receive the intervention

  • Internal comparison group

    • That is, the experience of those members

    of the cohort who are either unexposed or

    exposed to low levels can be used as the

    comparison group.

  • External comparison group

    • When the cohort is essentially homogeneous in

    terms of exposure to the suspected factor, a similar

    but unexposed cohort, or some other standard of

    comparison, is required to evaluate the experience

    of the exposed group.

    – People in employment from the same geographical area .

    – General population of the geographical area in which the

    exposed individuals reside.

  • Multiple comparison groups• When we can’t be sure that any single group

    will be sufficiently similar to the exposed

    group in terms of the distribution of potential

    confounding variables.

    • The study results may be more convincing if

    a similar association were observed for a

    number of different comparison groups.– an internal comparison groups (same factory but having different

    job) and the experience of general population (national and local

    rates) may be used.

  • Possible types of comparisons in

    cohort study

    Ex: association between antipsychotic drugs and hip

    fracture.

    General population (all elderly)

    - intervention vs. alternative intervention

    - intervention vs. no intervention

    Restricted population (elderly people with dementia)

    - intervention vs. alternative intervention

    - intervention vs. no intervention

  • BIAS

    Reliable (precise)

    Lack of random error

    Valid

    Lack of systematic errorReliable

    & valid

    Bias is a systemic error, rather than the random variation or

    lack of precision.

    Bias occurs in the recruitment of participants, the measurement

    of their risk factors and outcomes.

    Bias threatens study validity

  • Internal validity

    The internal validity of a study is defined as the

    extent to which the observed difference in

    outcomes between the two comparison groups can

    be attributed to the intervention rather than other

    factors.

  • Bias of Cohort Study

    • Selection Bias

    – Attrition bias

    – Healthy entrant effect

    – non-response bias

    • Information Bias

    – Response bias

    – Acertainment bias (detection bias)

    • Confounding

    – The effect or association between an exposure

    and outcome is distorted by the presence of

    another variable

  • Selection bias

    • Selection bias occurs when there is

    something inherently different between the

    groups being compared that could explain

    differences in the observed outcomes.

    • Loss to follow-up differs between exposed

    and not exposed (or between disease and

    no disease).

    • Follow up is usually easier in people who

    have been exposed to the exposure of

    interest.

  • Information bias• Collect different quality of information from

    exposed and not exposed groups

    (from participants or investigators).

    – Exposure ascertainment (response bias)

    under-reported the exposure behavior because

    they are aware that it can affect their health.

    – Diseases ascertainment (ascertainment bias,

    detection bias)

    diagnosis could have been influenced by

    knowledge of the study research hypothesis.

  • Confounding

    Exposure

    Confounder

    Disease

    The effect or association between an exposure and

    outcome is distorted by the presence of another variable

    ex: asthma and lung cancer (smoking is the confounder)

  • Confounding

    • Features of medical history—for example,

    stroke, osteoporosis

    • Exposure to drugs—for example,

    benzodiazepines,oestrogens

    • Demographics—for example, age and sex

    • Social and behavioural factors—for example,

    exercise and diet.atypical

    antipsychotic

    C

    Hip fracture

  • Differences in distribution of potential

    confounders

  • To deal with confounding

    Idea

    (hypothesis)

    Study

    design

    Statistical

    Analysis

    Matching

    RestrictionRandomization

    Stratification

    Regression

  • Matching & Restriction

    a 45-yr-old women with atypical antipsychotic

    a 45-yr-old woman with no intervention

    Matching

    Restriction

    ex: Only the elder are recruited

    ex: Only the older with dementia are recruited

    E

    C

    D

  • Patients taking atypical antipsychotics were over

    12 times more likely (63.1% vs. 4.7%) to have

    dementia.

    Restriction

  • Regression &

    stratification

  • ANALYSIS METHODS

  • Data preparation

  • Analysis methods• Cox proportional hazard regression (HR)

    – Time to an event (ex. time to hip fracture)

    – person-time information

    – time-varying covariates

    • Poisson regression

    – Count data

    • Logistic regression (RR)

    – Binary outcome (ex. occurrence of hip fracture)

    – No loss to follow up

    – Rare outcome

    – Person-time information not required

  • Interpretation of Hazard Ratio

    • HR = 0.5: at any particular time, half as many

    patients in the treatment group are

    experiencing an event compared to the control

    group.

    • HR = 1: at any particular time, event rates are

    the same in both groups,

    HR = 2: at any particular time, twice as many

    patients in the treatment group are experiencing

    an event compared to the control group.

  • Examples

  • Exposed Not Exposed

    Disease No

    diseaseDisease No

    disease

    Defines population

    (40 clinical centers in USA,

    50-79 yr-old postmenopausal women)

    Self selection

    Prosp.

    1993~

    1998

    Active or passive smoking

    Invasive breast cancer

    2009/8/14

  • Inclusion:

    93679 women

    aged 50~79 yr-

    old were

    recruited

    Exclusion:

    Had conditions

    that were

    predictive of

    survival less

    than 3 years

    Final subjects

    for analysis:

    93676 -> 79990

  • 1

    2

  • Which bias might the above cohort

    study have been prone to?

    (a) Non-response bias

    (b) Healthy entrant effect

    (c) Attrition bias

    (d) Response bias

    (e) Confounding

    (f) Allocation bias

  • 93 676

    12075 Cancer Hx.

    (12.9 %).

    (healthy entrant

    effect)

    443 loss to f/u

    (0.5 %).

    (attrition bias)

    1168 smoking status

    missing (1.25%).

    Under-report the

    exposure

    (response bias)

    79 990

    Non-response bias

  • (a) Non-response bias

    (b) Healthy entrant effect

    (c) Attrition bias

    (d) Response bias

    (e) Confounding

    (f) Allocation bias

    Exposure

    (smoking)

    Confounder

    (Alcohol intake)

    Disease

    (breast cancer)

    Allocation bias is mainly of concern in clinical trials.

    (to allocate people who they think would show the greatest

    benefit to a particular intervention)

    Which bias might the above cohort

    study have been prone to?

  • Advantages

    •Measure the effect of each variable on

    the probability of developing the outcome

    of interest (RR or HR).

    • A single study can examine various

    outcomes.

    Example: smoking vs. lung, cardiovascular, and

    cerebrovascular diseases.

  • Disadvantages

    • Expensive and time-consuming.

    • Inefficient when outcome is rare.

    • Loss to follow up can be a serious

    problem. The rarer the outcome the more

    significant the effect. (Attrition bias)

  • Thank you