Cohort Studies

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Introduction

The characteristic feature of a cohort study is that the investigator identifies subjects at a point in time when they do not have the outcome of interest and compares the incidence of the outcome of interest among groups of exposed and unexposed (or less exposed) subjects. (We can refer to the groups being compared as exposure cohorts.) Cohorts may be identified retrospectively or prospectively, but in either case the outcome status needs to be established at least twice. It must be established that a cohort did not have the outcome of interest at the beginning of the observation period, and the cohort needs to be examined again to determine whether or not the outcome subsequently developed, i.e., the incidence in each of the exposure groups.

Learning Objectives

Upon successful completion of this section of the course, the student will be able to:

- Prospective cohort study

- Retrospective cohort study

- Ambidirectional study 

- An internal comparison group

- An external comparison group

- A general population comparison group

Preview of Pre-Class Quiz #5

 

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Prospective Versus Retrospective Cohort Studies

There are two fundamental types of cohort studies based on when and how the subjects are enrolled into the study:

Prospective Cohort Studies:

Prospective.jpg In prospective cohort studies the investigators conceive and design the study, recruit subjects, and collect baseline exposure data on all subjects, before any of the subjects have developed any of the outcomes of interest. The subjects are then followed into the future in order to record the development of any of the outcomes of interest. The follow up can be conducted by mail questionnaires, by phone interviews, via the Internet, or in person with interviews, physical examinations, and laboratory or imaging tests. Combinations of these methods can also be used.

Typically, the investigators have a primary focus, for example, to learn more about cardiovascular disease or cancer, but the data collected from the cohort over time can be used to answer many questions and test many possible determinants, even factors that they hadn't considered when the study was originally conceived.

The Framingham Heart Study, Nurses Health Study, and Black Women's Health Study are good examples of large, productive prospective cohort studies. In each of these studies, the investigators wanted to study risk factors for common chronic diseases. The investigators identified a cohort (group) of possible subjects who would be feasible to follow for a prolonged period. Eligible subjects had to meet certain criteria (inclusion criteria) to be included in the study as subjects. The investigators then determine the initial or "baseline" characteristics, behaviors, and other "exposures" of all subjects at the beginning of the study. Information is collected from all subjects in the same way using exactly the same questions and data collection methods for all subjects. They design the questions and data collection procedures very carefully in order to have accurate information about exposures   before   disease develops in any of the subjects.

Of course, data analysis cannot take place until enough 'events' or 'outcomes' have occurred, so time must elapse, and the analyses will look at events that have occurred during the period of time from the beginning of the study until the time of the analysis or the end of the study. It goes without saying that analysis is always done retrospectively, because a span of time has to have elapsed before you can compare incidence. The thing that makes prospective cohort studies prospective is that they were designed prospectively, and subjects were enrolled and had baseline data collected before any of them developed any of the outcomes of interest. Determining baseline exposure status before disease events occur gives prospective studies an important advantage in reducing certain types of bias that can occur in retrospective cohort studies and case-control studies, though at the cost of efficiency.

paste_image47.jpg After baseline information is collected, subjects in a prospective cohort study are then followed "longitudinally," i.e. over a period of time, usually for years. This enables the investigators to know when follow up began, if and when subjects become diseased, if and when they become lost to follow up, and whether their exposure status changed during the follow up period. By having individual data on these details for each subject, the investigators can compute and compare the incidence rates for each of the exposure groups. The illustration to the right shows a hypothetical group of 12 subjects followed over a number of years. They were enrolled into the study at different times, and some of them became lost to follow up, i.e., they stopped responding to letters, emails and phone calls, so we don't know what happened to them; these are show by the horizontal follow up line stopping. Three subjects developed the outcome of interest at the approximate dates show by the "X"s. The incidence rate was calculated by computing the disease free observation time for each subject, adding up the disease-free observation times for the entire group, and then dividing this into the number of events, as shown in the calculation below the time line.

Since the investigators asked about many exposures during baseline data collection, they can eventually use the data to study many associations between different exposures and disease outcomes. For example, one could identify smokers and non-smokers at baseline and compare their subsequent incidence of developing heart disease. Alternatively, one could group subjects based on their body mass index (BMI) and compare their risk of developing heart disease or cancer.

 

RateRatio_NursesStudy.jpg The data to the left is from a paper from the Nurse's Health Study in which they examined the association of body mass index (BMI) with heart disease. They created five exposure groups, based on BMI and followed about 118,000 nurses. In this case they used the incidence rate of myocardial infarctions (MI, i.e., heart attacks) in the leanest women (BMI < 21) as a reference, against which they compared the incidence rates of MI in the other four groups. For example, the incidence rate of MI in the reference group (those with BMI < 21) was 23.1 per 100,000 person-years of disease-free observation time. The incidence rate in the heaviest group (BMI > 29) was 85.4 MIs per 100,000 person-years.

Manson et al. also used the Nurses' Health Study (NHS) to examine the effect of exercise on cardiovascular disease. The NHS enrolled 121,700 female RNs in 1976, but they didn't begin to collect information on exercise until 1986. Since the original baseline data did not include information on exercise, the exercise study only used the women who had not yet developed any cardiovascular problems by 1986. So, the exercise study was restricted to the 72,448 subjects who were free of cardiovascular disease and cancer in 1986. In essence, the information on exercise and activity that they began collecting in 1986 represented a new baseline for this subset of the original cohort.

Retrospective Cohort Studies

Retrospective_Cohort.jpg Retrospective studies also group subjects based on their exposure status and compare their incidence of disease. However, in this case both exposure status and outcome are ascertained retrospectively. In essence, the investigators jump back in time to identify a useful cohort which was initially free of disease and 'at risk.' They then use whatever records are available to determine each subject's exposure status at the begin of the observation period, and they then ascertain what subsequently happened to the subjects in the two (or more) exposure groups. Retrospective cohort studies are also 'longitudinal,' because they examine health outcomes over a span of time. The distinction is that in retrospective cohort studies all of the cases of disease have already occurred before the investigators initiate the study. In contrast, exposure information is collected at the beginning of prospective cohort studies before any subjects have developed any of the outcomes or interest, and the 'at risk' period begins after baseline exposure data is collected and extends into the future.

Retrospective cohort studies are particularly useful for unusual exposures or occupational exposures. For example, if an investigator wanted to determine whether exposure to chemicals used in tire manufacturing was associated with an increased risk of death, one might find a tire manufacturing factory that had been in operation for several decades. One could potentially use employee health records to identify those who had had jobs which involved exposure to the chemicals in question (e.g., workers who actually manufactured tires) and non-exposed coworkers (e.g., clerical workers or sales personnel in the same company or, even better, workers also involved in manufacturing operations but with jobs that didn't involve exposure to the chemicals). One could then ascertain what had happened to all the subjects and compare the incidence of death in the exposed and non-exposed workers.

Retrospective cohort studies like this are very efficient because they take much less time and cost much less than prospective cohort studies, but this advantage also creates potential problems. Sometimes exposure status is not clear when it is necessary to go back in time and use whatever data was available, because the data being used was not designed to be used in a study. Even if it was clear who was exposed to tire manufacturing chemicals based on employee records, it would also be important to take into account (or adjust for) other differences that could have influenced mortality (confounding factors). For example, in a study comparing mortality rates between workers exposed to solvents used in tire manufacture and an unexposed comparison group, it might be important to adjust for confounding factors such as smoking and alcohol consumption. However, it is unlikely that a retrospective cohort study would have accurate information on these other risk factors.

paste_image45.jpg When an outbreak of Giardia (see this CDC link) occurred in Milton, MA, the Milton Health Department requested assistance from the epidemiologists in the MA Department of Public Health. (Kathleen MacVarish from the BUSPH Practice Office was the Health Agent in Milton who led the investigation.) The request for assistance was made some time after the start of the outbreak, and the outbreak was winding down by the time DPH began their study. The outbreak was clearly concentrated among members of the Wollaston Golf Club in Milton, MA, which had two swimming pools, one for adults and a wading pool for infants and small children. Given what they knew about the usual mechanisms by which Giardia is transmitted, the investigators thought that contamination of the kiddy pool by a child shedding Giardia into their stool was the most likely source. (NOTE) The study was conducted by getting most of the people in the cohort to complete a questionnaire in which one of the key questions was "Did you spend any time in the kiddy pool?" This outbreak clearly took place in a well-defined cohort (members of the club), and the investigators could determine how many people developed Giardia in each of the exposure groups (i.e., exposed to the kiddy pool or not). Moreover, they also knew how many respondents had been exposed to the kiddy pool and how many were not. In other words, they knew the denominators for the exposure groups, so they could calculate the cumulative incidence, risk difference, and the risk ratio. They found that people who had spent time in the kiddy pool had 9.0 more cases per 100 persons than those who spent time in the kiddy pool. The risk ratio was 3.27. Because the investigation started after the cases had already occurred, DPH's study of Giardia in Milton is an example of a retrospective cohort study.

An Ambidirectional Cohort Study

A cohort study may also be   ambidirectional , meaning that there are both retrospective and prospective phases of the study. Ambidirectional studies are much less common than purely prospective or retrospective studies, but they are conceptually consistent with and share elements of the advantages and disadvantages of both types of studies. The Air Force Health Study (AFHS) - also known as the Ranch Hand Study - was initiated by the U. S. Air Force in 1979 to assess the possible health effects of military personnel's exposure to Agent Orange and other chemical defoliants sprayed during the Vietnam War. The study was conducted comparing:

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This is an "ambidirectional" study, because it had both a retrospective component and a prospective component. Some of the problems suspected to be caused by Agent Orange would have occurred shortly after exposure (e.g., skin rashes). These were addressed by looking at the cohort retrospectively to see if the exposed pilots had had more problems than the controls. Other problems (e.g., infertility & cancer) might not surface until some time after the exposure. Therefore, the cohort was followed prospectively to see if they had a greater incidence of these problems. The reports that emerged from the study suggested links between Agent Orange exposure and nine distinct diseases: chloracne, Hodgkin's disease, multiple myeloma, non- Hodgkin's lymphoma, porphyria cutanea tarda, respiratory cancers (lung, bronchus, larynx and trachea), soft-tissue sarcoma, acute and subacute peripheral neuropathy, and prostate cancer. 

Closed (Fixed) versus Open Cohorts

A closed cohort is one with fixed membership. Once the cohort is defined by enrolling subjects and follow up begins, no one can be added. The number of subjects may decline because of death or loss to follow up, but no additional subjects are added. As a result, closed cohorts always get smaller over time. Citizens of Japan who were exposed to radiation when atomic bombs were dropped on Hiroshima and Nagasaki during the second World War, would be considered members of a fixed or closed cohort that was defined by an event. Ashengrau and Seage would classify the bombing victims as a "fixed cohort" and make a distinction between a fixed cohort and a closed cohort. They define a closed cohort as similar to a fixed cohort except that a closed cohort is one that has no losses to follow up, for example, a cohort of people who attended a luncheon that resulted in an outbreak of salmonellosis.

In contrast, an open cohort is dynamic, meaning that members can leave or be added over time. Rothman gives the example of a state cancer registry. Subjects are continually added when they are diagnosed with cancer, so new subjects are continually added. Subjects can also leave the cohort by moving to a new state or dying. Another example of an open or dynamic cohort would be students at Boston University.

These descriptions should sound familiar, because they essentially parallel the descriptions of fixed and dynamic populations from the Measures of Disease Frequency module.   The great majority of cohort studies are conducted in closed (or fixed) cohorts, because it is more difficult to establish eligibility and track people in an open cohort, since they can enter and leave at any time.   This problem becomes greater as the size of the cohort gets larger and/or the study continues for a longer period of time.   Note that the retrospective cohort study of Giardia in Milton was an open cohort (members of the golf club), but the population was relatively small and time period very short.

Selection of Subjects

General Population Cohorts versus Special Exposure Cohorts

For common risk factors, (e.g., smoking, obesity) investigators may enroll a general population cohort, e.g.,

Once a general population cohort is enrolled, investigators will ascertain their baseline exposures to a large number of exposures of interest and possible confounding factors that they may need to adjust for in the analyses.

For uncommon risks, investigators use special exposure cohorts, e.g.,

The Comparison Group

The ideal comparison group in a cohort study would be a group that was exactly the same as the exposed group, except that they would be unexposed. This is referred to as the "counterfactual ideal," because it is impossible for the same person to be both exposed and unexposed at the same time. Consequently, the best one can do is to select a comparison group that differs with respect to the exposure of interest but is a similar as possible with respect to other factors that might influence the outcome. There are two key things that are essential in selecting the comparison group in a cohort study:

There are three general types of comparison groups for cohort studies.

  1. An internal comparison group
  2. A comparison cohort
  3. The general population

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An internal comparison group consists of unexposed members of the same cohort. This is generally the best comparison group, because the subjects are comparable in many respects. For example, as noted earlier, the Nurses' Health Study, used the cohort to study a possible association between obesity and myocardial infarction. Subjects from the cohort were categorized into one of five levels of body mass index, and the group with the lowest BMI was used as an internal comparison group or reference group, against which the other categories were compared.

 

 

 

 

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When it isn't possible to take a well-defined cohort and divide it into exposure groups, sometimes one can identify an   external comparison cohort . This type of comparison group was used when researchers wanted to look at occupational exposure to disulfide in rayon factory workers. Because virtually all workers in the plant were exposed to disulfide, it was not possible to use an internal comparison group from the same plant. Instead, they selected a group of people employed in a paper mill as an external comparison cohort. Both groups had similar education, age, socioeconomic status, and gender distribution. However, they may have differed with respect to other important confounding factors.

GenPopulation_ComparisonGroup.jpg The third possibility is to use the general population as a comparison group. This works best where only a small percentage of the population would be exposed, as with a specific occupational exposure. The main advantage is the availability of data (if one is looking at mortality from different causes or cancer incidence, which are the two outcomes almost universally available in countries like the United States . One study looked at mortality rates of workers in the rubber industry and compared them to the general population of the US. There are several problems with this. 1) Some of the general population will have had the exposure (same occupation); 2) the general population includes people who are unable to work because of illness or disability. Employed workers tend to be healthier than the general population. This is a well-documented phenomenon known as the "healthy worker effect." Rates of disease and death tend to be higher in the general population than in the employed work force because the general population includes many people who are too sick or disabled to work. As a result, even if the exposure was, in fact, associated with higher mortality, the magnitude of association would be underestimated because of the inherently higher mortality rate in the general population (which includes both employed and unemployed workers).   Although this is not a problem with all diseases, the general population generally exhibits the greatest departure from the counterfactual ideal, and therefore is less widely used today than in the past. Another notable disadvantage of the general population comparison group is that data on important confounders are almost never available.  

The use of the general population as a comparison group is most likely to be seen today in descriptive epidemiology, particularly when there are many categories of exposure with only a small number of outcomes per category. For example, the Massachusetts Cancer Registry reports the cancer rate in each of 351 cities and towns using the overall rate in the general population as a comparison.   Similarly, descriptions of occupational mortality based on death certificate data may have hundreds of different occupations and also use the general population as a comparison group.  

Selection Bias in Cohort Studies 

Selection bias from   enrollment   procedures rarely occurs in cohort studies, because the outcomes have not yet occurred at the time when subjects are enrolled, so a potential participant's eventual outcome status is unknown and therefore can not influence . However, selection bias can occur in a prospective cohort study as a result of   differences in retention during the follow-up period after enrollment.   When the observation period spans many years (in either retrospective or prospective cohort studies) it can be difficult to track subjects for the entire study. Subjects may disappear as a result of death, relocation, or (in prospective studies) loss of interest in the study. Studies with follow up rates of less than 60% will generally be seen as having limited validity, but even losses of 20% can introduce bias if the reasons for loss are related to both exposure status and outcome status.  

Losses to follow-up can introduce bias (a deviation of the observed value of the measure of association from the value that would have been observed in the absence of bias) if there are   differences   in likelihood of loss to follow-up that are related to exposure status   and   outcome. In general, large prospective cohort studies are doing well if they can maintain follow-up of 80-90% of their sample for long periods. As an illustration of how bias can be introduced with loss to follow-up, consider the following example. Suppose investigators were studying the association between use of oral contraceptives and development of thromboembolism [i.e., blood clots in veins of the lower extremities or pelvis that can break loose and become lodged in the branches of the pulmonary artery]. Suppose, 20/10,000 OC users developed thromboembolism, but only 10/10,000 controls did, i.e., OC users really had a 2-fold greater risk. If roughly 4,000 subjects were lost to follow-up in each group, and if 12 of the 20 subjects who developed thromboembolism in the OC group became lost to follow-up, but only 2 subjects with thromboembolism were lost in the control group, the differential loss to follow-up would make it appear that rates of thromboembolism were similar, and the estimate of association (risk ratio) would be biased.

The bias that can result from the differential follow up described above is a type of selection bias, which is discussed in the module on bias.

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On the other hand, it is also important to remember that even substantial loss to follow-up (LTF) does not guarantee that bias will necessarily occur. If LTF occurs in a manner in which those who are LTF in each exposure group have the same rate of outcome as those who remain, there will be no bias. Nevertheless, as the proportion of study participants who are LTF increases, both the likelihood of bias and the probability that the extent of bias will be substantial also increase. Therefore, researchers do their best to reduce LTF by maintaining contact with participants at regular intervals, collecting information on friends or relatives that would know how to reach a participant should s/he move, using the National Death Index and other databases to track the vital status of participants who do not respond to attempts at contact, as well as other strategies. Most of these strategies are only applicable to prospective cohort studies, because all the follow-up time has already occurred in a retrospective cohort study before the investigators get involved.

Carefully done prospective cohort studies will go to extraordinary lengths to maintain high follow-up rates.

Ways to Maintain Follow Up

  1. Collect baseline information that will facilitate tracking subjects, e.g., addresses, phone numbers and email addresses not only for the subject, but also for possible contacts such as next of kin or close friends.
  2. When feasible, use subjects who are easier to track. Studies sometimes use doctors or nurses or other professionals because they are more likely to remain interested in the study, and because they belong to professional organizations that make it easier to track them down if they relocate.
  3. Maintain regular contact via personal contact, mail, phone, or email.
  4. Send participants newsletters periodically to keep them updated on the study' progress.
  5. Send multiple requests to non-responders.
  6. Employ tracking resources, such as telephone directories, the US Postal Service's National Change of Address system, or Internet tracking resources.

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Unlike the bias that can occur from differential LTF, selection bias at   enrollment   rarely occurs in cohort studies, because the outcomes have not yet occurred at the time when subjects are enrolled, so a potential participant's eventual outcome status is unknown and therefore can not influence their participation. This is even more unlikely in prospective than retrospective cohort studies, although even in the latter the cohort is almost always created based on information that was recorded prior to the development of the outcome.

 

Non-participation in a Prospective Cohort Study

Ordinarily, some of the individuals invited to be subjects in a prospective cohort study refuse to participate. Many students mistakenly have the impression that this in itself constitutes bias. Suppose 100,000 subjects are invited to be in a study on the association between smoking and risk of heart attack, but only 50,000 agree to participate. Only 20% of those who agree are smokers versus 30% in those who refuse. The frequency of smoking in the study subjects is not representative of its prevalence in the population, but you can still compare smokers and non-smokers with respect to the incidence of myocardial infarction.

Key Questions You Should Ask When Reading a Cohort Study:

Advantages & Disadvantages of Cohort Studies

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Advantages

 

1. Cohort studies more clearly indicate the temporal sequence between exposure and outcome, because in a cohort study, subjects are known to be disease-free at the beginning of the observation period when their exposure status is established. In case-control studies, one begins with diseased and non-diseased people and then asks about their prior exposures. This is a reasonable approach to establishing past exposures, but sometimes people's memories are inaccurate. Certainly, in a prospective cohort study there is the advantage that you can securely establish that all subjects are free of disease as they enroll into the study, and one can assess there exposure status at the same time, so there is an opportunity to accurately ascertain exposure status at the outset and document the absence of disease. Therefore, if persons with the exposure develop the disease, it is clear that the exposure preceded the disease and could potentially be causally related.

2. Cohort studies allow you to calculate the incidence of disease in each group, so you can calculate:

3. While a cohort design can be used to investigate common exposures (e.g., risk factors for cardiovascular disease and cancer in the Nurses' Health Study), they are particularly useful for evaluating the effects of rare or unusual exposures, because the investigators can make it a point to identify an adequate number of subjects who have an unusual exposure, e.g.,

4. A cohort study also enables examination of multiple outcomes of a single risk factor.

5. Cohort studies, especially prospective cohort studies, reduce the possibility that the results will be biased by selecting subjects for the comparison group who may be more or less likely to have the outcome of interest, because in a cohort study the outcome is not known at baseline when exposure status is established.

The "Air Force Health Study" on agent orange illustrates these advantages.

  • It was clear that the exposure preceded adverse outcomes among exposed subjects who developed problems.
  • It was used to evaluate the effects of an unusual risk factors (agent orange).
  • It allowed direct calculation of incidence rates.
  • It enabled the investigators to study multiple outcomes of this single unusual exposure.
  • The prospective component of the study was not biased by knowledge of outcome status, because the outcomes hadn't occurred at the time of enrollment.

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Pitfalls:

Disadvantages of Prospective Cohort Studies

  1. You may have to follow large numbers of subjects for a long time.
  2. They can be very expensive and time consuming.
  3. They are not good for rare diseases.
  4. They are not good for diseases with a long latency.
  5. Differential loss to follow up can introduce bias.

Disadvantages of Retrospective Cohort Studies

  1. As with prospective cohort studies, they are not good for very rare diseases.
  2. If one uses records that were not designed for the study, the available data may be of poor quality.
  3. There is frequently an absence of data on potential confounding factors if the data was recorded in the past.
  4. It may be difficult to identify an appropriate exposed cohort and an appropriate comparison group.
  5. Differential losses to follow up can also bias retrospective cohort studies.

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