Epid 7010

Cohort Studies

Monday, September 19, 2011

Experimental Studies Review

Disadvantages of experimental studies
High Cost Limited Generalizability to other populations Ethical Issues Non-compliance of treatment or control group

Advantages of experimental studies

Scientically rigorous Provide the best evidence for causality

Monday, September 19, 2011

Todays Objectives
Learn what an observational studies are, and how they differ from experimental studies Understand issues related to the unexposed population Understand some of the data sources we use Know what the differences are between a prospective and retrospective cohort study Know the advantages and disadvantages of cohort studies

Monday, September 19, 2011

Observational Studies
Investigator is a passive observer Only ethical method for studying harmful exposures Generally less expensive and more practical to perform than experiments These are population based, and thus more likely to be generalizable than experimental studies

Monday, September 19, 2011

Observational Studies
Hallmark of experimental studies is:
Investigators assign exposure

In observational studies we observe populations of exposed and unexposed and compare them by disease incidence Or we may look at diseased and nondiseased populations and compare their exposure status

Monday, September 19, 2011

Cohort Studies
Compare exposed and unexposed populations, and compare their disease incidence We choose the exposed and unexposed populations, but we dont assign that exposure An advantage and disadvantage are immediately clear
Is this a good study type if the exposure is rare? Is this a good study type if the disease is rare?

Monday, September 19, 2011

Rare Exposure/Rare Disease

An advantage and disadvantage are immediately clear

Is this a good study type if the exposure is rare?
Yes. We are seeking out the exposed and unexposed populations. If the exposure is rare, we just expend more effort to nd exposed individuals.

Is this a good study type if the disease is rare?

Not really. We wait for incident disease to occur. If we dont get many cases of disease, the exposure will show little effect. A rare disease greatly increases the number of subjects we need to enroll, or the time of follow-up
Monday, September 19, 2011

Exposure
Exposure Classication
Usually split the exposed group into several smaller groups based on exposure status
ie light smoker, moderate smoker, heavy smoker Also identify other exposures that may confound the main exposure you are interested in (age, gender etc.)

Unexposed group, also called the referent group

If they become exposed during follow-up, their person-time as unexposed ends and they start contributing person-time to the exposed group Keep the induction period in mind - if it is known that disease D shows up at a minimum of 10 years post exposure to X, than those exposed to X for under 10 years should be considered unexposed Why? Because any occurrence of D before 10 years cannot have been caused by X
Monday, September 19, 2011

Choice of Referent Group

Choice of Referent Group
Want the unexposed group to be as similar to the exposed group as possible (especially for factors such as gender, age, occupation etc.)
If you are studying the occurrence of Reyes syndrome in children with inuenza who were given aspirin, you would want the referent group to be children who had inuenza during a similar time period but did not receive aspirin If you are studying chemical exposures among factory workers, you would want the referent group to be workers in the same factory who were not exposed These are examples of internal comparison groups

Monday, September 19, 2011

Choice of Referent Group

Choice of referent group
If an internal group is not possible, than an external comparison group can be used for instance almost every child with a certain condition receives a certain treatment that is your exposure, or all workers in the factory have some level of exposure, This group can be the general population, or some other population subset without the exposure of interest

Monday, September 19, 2011

Choice of Referent Group

Disadvantages of external comparison groups
The general population may differ signicantly from the exposed group in relation to factors other than the exposure
The Healthy Worker Effect - In studies of workplace exposures, the general population has been found to be an unt comparison group. This is because people who are able to work are on average more healthy than any randomly chosen group from the general population. Therefore, any measure of the harmfulness of a workplace exposure relative to the general population will be underestimated (RR closer to 1 than it should be)

If another subset of the population is chosen as the referent, you have to be concerned that the subset has unique exposures that must be accounted for
Especially when these exposures may also cause the disease you are studying

Monday, September 19, 2011

Data
Data Sources
Always consider the source of data in a study Workplace records, school records, medical records etc. have the advantage of being recorded before the outcome occurs
Allows accurate calculation of person-time at risk Dont have to rely on the recall of an individual These records may not have the amount of detail you would like to conduct a study

Monday, September 19, 2011

Data Sources
Interviews can be a good source of data
Better in prospective than retrospective studies. In prospective studies you are interviewing subjects at set intervals and you do not need to worry about fading memories of certain events In a retrospective study, you worry about the accuracy of recall of past exposures Also subject to recall bias - this phenomenon occurs because sick individuals are more likely to remember past exposures than well individuals

Monday, September 19, 2011

Prospective and Retrospective

Prospective Cohort Study
Exposed and referent populations are identied and followed until outcomes occur

Retrospective Cohort Study

Exposure and outcome have already occurred Timing of exposure is known relative to the outcome An example would be an identication of a medical or surgical exposure from medical records, and then looking to see if a certain outcome occurred later on

Monday, September 19, 2011

Prospective and Retrospective

Prospective
Long wait time More expensive Data collected specically for the study New data can be collected if necessary (e.g. blood samples for specic tests) Less prone to bias

Retrospective
Little or no wait time Less expensive Measures of effect can be calculated as in prospective study Data were not originally collected for study purposes and thus may be incomplete Prone to information bias

Monday, September 19, 2011

Example: Vaccination and Autism

The Study: A Population-Based Study of MMR Vaccination and Autism. Madsen et al. NEJM Nov 7, 2002. Study Design: Retrospective Cohort Study Study Population: 537,303 children born in Denmark between 1991 and 1998 (this is every child born in Denmark during that period)

Monday, September 19, 2011

Vaccination and Autism

Sources of Data:
Population registry updated weekly with the identities of all live-born children and new residents of Denmark Exposure Status to MMR vaccine determined by linkage of the population registry data with the National Health of Health which records all vaccination info for Danish children
98.5% of all children in the cohort had their vaccination status veried in this way. The additional 1.5% were veried via different methods.

Monday, September 19, 2011

Vaccination and Autism

Sources of Data:
Outcome Status determined from national psychiatric records . Only psychiatrists are allowed to enter a diagnosis of autism in this registry

Follow-up (retrospective follow-up):

Began at age 1 ended with the diagnosis of autism or associated disorders, competing risks, or December 31, 1999.

Monday, September 19, 2011

Vaccination and Autism

Quick Review:
Is this a xed, closed, or open cohort?
Open since individuals were able to enter and exit the cohort between 1991 and 1999

Is the referent group an internal or external comparison group?

Perhaps a debatable answer. Both the exposed and unexposed groups are all children born in Denmark during a set time period, therefore you could say there is an internal comparison group However, a better internal group might be children seen at a vaccination clinic who did not receive MMR. So an argument could be made that this is a population based comparison group
Monday, September 19, 2011

Vaccination and Autism

Results from table 2:
Status Autistic Person-Time

Vaccinated

Unvaccinated

263 53

1,647,504 482,360

What kind of measure was this study designed to calculate? Is this a good measure with this type of cohort?

Monday, September 19, 2011

Vaccination and Autism

Measures: The authors had person-time data so the incidence rate (IR) could be calculated. Is this an appropriate measure for this study design?
The population is open. The unexposed population can also contribute person-time to the exposed population if they get vaccinated during the follow-up period. This makes the IR more appropriate than the CI.

Monday, September 19, 2011

Vaccination and Autism

Incidence rates:
Exposed: 263 cases/ 1,647,504 person-years = 16 cases per 100,000 person-years Unexposed: 53 cases/ 482,360 person-years = 11 cases per 100,000 person-years

Monday, September 19, 2011

Vaccination and Autism

Measures of Association
IRR and IRD IRR = 16/11 = 1.45 IRD = 16 - 11 = 5 cases per 100,000 person- years Interpretations, IRR: Cases occurred 1.45 times as frequently in vaccinated vs. unvaccinated children. Or, cases occurred 45% faster (or more often) in the vaccinated vs. the unvaccinated. Or, if you are interpreting the IRR as a risk ratio, those vaccinated were 1.45 times as likely to develop autism as the unvaccinated.

Monday, September 19, 2011

Vaccination and Autism

Measures of Association
IRR and IRD IRR = 16/11 = 1.45 IRD = 16 - 11 = 5 cases per 100,000 person- years

So for each 100,000 children vaccinated each year, you will see 5 more cases of autism than in those who are unvaccinated Attributable Fraction: RD/Re = 5/16 = 32% 32% of the autism in the vaccinated can be attributed to the vaccine
Monday, September 19, 2011

Vaccination and Autism

Discussion
These results I presented are crude results. It simply compares the total incidence rate in the exposed to the IR in the unexposed. It does not adjust for any factors that might be different between the two groups. For instance the age, sex, birth weight and other factors potentially related to the outcome were not similar between the two groups. These factors are related to the outcome, and are clearly associated with the exposure in terms of their distribution in the data. When these factors were adjusted for, the association disappeared and the IRR was 0.92, indicating essentially no effect of vaccination on autism
Monday, September 19, 2011

Vaccination and Autism

Discussion contd:
The effect that the extraneous factors had on the IRR and IRD is known as confounding, and is something we will discuss in detail later. Confounding is a major complication of observational studies since people may choose to be in a particular exposure group for reasons that may relate to the outcome Confounding is what is reduced in experimental studies by randomizing assignment to the exposure groups.

Monday, September 19, 2011

Cohort Study Wrap-up

Advantages Temporality can be established Direct calculation of risk/rate ratio Efcient for rare exposures Can yield information on multiple exposures Can examine multiple outcomes Can observe natural history of disease Easier to generalize results to the population at large than with most experiments Disadvantages Time-consuming Expensive Often require large sample size Not efcient for rare outcomes Losses to follow-up may introduce bias Exposure status may change during course of study Must be able to identify and control for as many confounders as possible No way to control for unknown confounders

Monday, September 19, 2011

Learning Objectives
Learn what an observational studies are, and how they differ from experimental studies Know the difference between an open and closed cohort Understand issues related to the unexposed population Understand some of the data sources we use Know what the differences are between a prospective and retrospective cohort study Know the advantages and disadvantages of cohort studies

Monday, September 19, 2011