Cohort Studies Compare incidence Cohort Study Follow up

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Cohort Studies

Cohort Studies

Compare incidence Cohort Study • Follow up studies • Longitudinal studies • Incidence studies

Compare incidence Cohort Study • Follow up studies • Longitudinal studies • Incidence studies Identify non-diseased people; group by risk factor status Compare past exposures Compare their past exposures. X X Follow longitudinally to compare incidence. X X XX Case – XXX X Control Study Find cases with disease & non-disease controls.

Key Features of Cohort Studies • Start with non-diseased people. • Group by exposure

Key Features of Cohort Studies • Start with non-diseased people. • Group by exposure status. • Compare incidence of disease. X Exposed Non-diseased initially Not Exposed Time passes X X X Compare Incidence

In prospective cohort studies conception, design, & enrollment occur before anyone develops the outcome.

In prospective cohort studies conception, design, & enrollment occur before anyone develops the outcome. Enroll non-diseased subjects; collect baseline exposure data X X Compare incidence X Obese X Follow up at intervals to get accurate outcome data. Lean Identify a cohort retrospectively, e. g. employees at a tire factory. Exposed to chemicals Non-exposed office workers Determine what then happened to them. X X X Compare incidence X

A randomized clinical trial is similar to a prospective cohort study. The investigators assign

A randomized clinical trial is similar to a prospective cohort study. The investigators assign subjects to a treatment or intervention. Aspirin X Compare incidence over time Placebo X X X

Club Members Had factor Didn’t have factor Kiddy Pool No Kiddy Pool Compare Incidence

Club Members Had factor Didn’t have factor Kiddy Pool No Kiddy Pool Compare Incidence Start of Study Past During the short time course of this study fairly reliable data was collected by interviews with club members.

Employees of tire manufacturer Had factor Didn’t have factor Tire makers Clerical staff Compare

Employees of tire manufacturer Had factor Didn’t have factor Tire makers Clerical staff Compare Incidence of Death Start of Study Past During the long time course of this occupational study data on exposure was from employee records and there was little information on other confounding factors.

Patients with ankylosing spondylitis Had factor Didn’t have factor X-Ray therapy Otherapy Compare Incidence

Patients with ankylosing spondylitis Had factor Didn’t have factor X-Ray therapy Otherapy Compare Incidence of Cancer Start of Study Past During the long time course of this medical study accurate data on exposure was obtained from medical records, but accurate information about smoking, alcohol consumption, BMI, & occupational exposures was missing.

Data Sources for Retrospective Cohort Studies Retrospective cohort studies are useful for unusual exposures

Data Sources for Retrospective Cohort Studies Retrospective cohort studies are useful for unusual exposures and they are efficient for diseases with long latent periods (time between exposure & disease). • • • Questionnaires Employee records Medical records However, accurate information on the main exposure and confounding factors is often missing because the data source was not designed for the purpose of conducting the study.

Similar in Design & Analysis • Retrospective Cohort • Prospective Cohort • Clinical Trial

Similar in Design & Analysis • Retrospective Cohort • Prospective Cohort • Clinical Trial • You can collect data in a spreadsheet. • Organize findings in a 2 x 2 table (or R x C). • Calculate RR, RD, AR% • Test for significance with chi square. • Compute 95% confidence interval for RR.

Recording the data for analysis: A table with subjects in rows. Exposures and outcomes

Recording the data for analysis: A table with subjects in rows. Exposures and outcomes are listed in columns.

Analysis of Retrospective Cohort Studies Given the assumption that exposure status is fixed and

Analysis of Retrospective Cohort Studies Given the assumption that exposure status is fixed and the lack of periodic follow up, it makes sense to compare cumulative incidence.

Got Giardiasis Yes Cumulative Incidence No In kiddy pool Yes 16 108 124 12.

Got Giardiasis Yes Cumulative Incidence No In kiddy pool Yes 16 108 124 12. 9% Not exposed No 14 341 355 3. 9% 12. 9% Relative Risk = = 3. 3 ( 1. 7 -6. 5) 3. 9% P value = 0. 0003

Prospective Cohort Study The Cohort 117, 000 Nurses without cancer or CVD Have risk

Prospective Cohort Study The Cohort 117, 000 Nurses without cancer or CVD Have risk factor obese Don’t have it lean Start of Study Compare Incidence of disease Follow-up Future A major advantage of prospective cohort studies is that they are carefully designed with specific goals in mind. Therefore, information on baseline exposures can be carefully collected on all subjects before anyone has an “event”.

Potential Sources of Data in a Prospective Cohort Study • • • Interviews •

Potential Sources of Data in a Prospective Cohort Study • • • Interviews • • Imaging studies (x-ray, ultrasound, CT, etc. ) Questionnaires Biological specimens (blood, urine, toenails, hair) Medical records (verifying outcomes such as myocardial infarction, stroke, cancer, etc. ) Data collected specifically for a prospective cohort study will be of higher quality than that obtained from pre-existing records, but it is more expensive to do a large, prospective cohort study.

Potential Problems • Loss to follow up. If follow up is over many years,

Potential Problems • Loss to follow up. If follow up is over many years, subjects may loose interest and quit. • Exposure status may change. What if some women lost or gained a substantial amount of weight during the period of study? What if smokers quit? These problems can be overcome by taken steps to minimize loss to follow-up and by careful periodic follow up with re-assessment of exposure status.

Incidence Rate For Variable Followup in A Prospective Cohort Study Subject ABCDEFGHIJKL 81 82

Incidence Rate For Variable Followup in A Prospective Cohort Study Subject ABCDEFGHIJKL 81 82 x= when they got disease Time at Risk 8. 3 11. 0 14. 0 10. 2 3. 0 x x 12. 0 7. 0 10. 0 3. 0 9. 0 6. 2 x 83 84 85 86 87 88 89 90 91 92 93 94 95 Incidence (IR) = 3/107. 7 =. 028/ person-yr Total time at risk =107. 7 = 28/1000 p-yrs person-yrs

Nurses Health Study Is obesity associated with an increased risk of heart disease? BMI:

Nurses Health Study Is obesity associated with an increased risk of heart disease? BMI: <21 21 -<23 MI Rate per # MIs person-years 100, 000 P-Yrs Relative (non-fatal) of observation (incidence) Risk 41 177, 356 23. 1 1. 0 57 194, 243 29. 3 1. 3 23 -<25 56 155, 717 36. 0 1. 6 25 -<29 67 148, 541 45. 1 2. 0 >29 85 99, 573 85. 4 3. 7 Risk difference = 62. 3 excess cases /100, 000 P-Yrs

Another Unusual Risk Factor Agent Orange Veterans’ Problems after Viet Nam: • Skin rashes

Another Unusual Risk Factor Agent Orange Veterans’ Problems after Viet Nam: • Skin rashes • Psychological problems • Infertility • Liver abnormalities • Cancers

Goals of the Agent Orange Study Look at a single, unusual exposure. Look at

Goals of the Agent Orange Study Look at a single, unusual exposure. Look at multiple possible effects.

An Ambi-directional Cohort Study The “Ranch Hand” study looked at effects of Agent Orange

An Ambi-directional Cohort Study The “Ranch Hand” study looked at effects of Agent Orange » 1, 264 pilots who sprayed dioxin in Vietnam » 1, 264 pilots who flew only cargo missions in Vietnam Prospective part Retrospective part Incidence of cancer? Exposed Unexposed Incidence of skin rash? Start of Study

Why were pilots flying only cargo missions an appropriate comparison groups?

Why were pilots flying only cargo missions an appropriate comparison groups?

A cohort study can look at multiple effects of a single exposure. Yes Skin

A cohort study can look at multiple effects of a single exposure. Yes Skin Disease Abnormalities Yes Liver No Problems Yes Psychological No Cancer Yes No 139 Agent Orange 119 Yes No 169 No 239 3 217 10, 820 227 10, 807 98 138 Subjects grouped by risk factor status

Conclusions from the Ranch Hand Study Exposure to dioxin was associated with a significant

Conclusions from the Ranch Hand Study Exposure to dioxin was associated with a significant increase in risk of soft tissue sarcoma, non-Hodgkin's lymphoma, and Hodgkin's disease. There was suggestive, but not statistically significant evidence of an association with respiratory cancers, prostate cancer, and multiple myeloma.

Selecting Subjects for a Cohort Study Common risk factors (obesity, HBP): • A cohort

Selecting Subjects for a Cohort Study Common risk factors (obesity, HBP): • A cohort from the general population: (e. g. , Framingham Heart Study) • A special study group: doctors, nurses (e. g. The Nurse’s Health Study) Unusual risk factors: • A special exposure group: (e. g. , tire manufacturing, dioxin, asbestos)

The Comparison Group 1) As similar as possible with respect to other factors that

The Comparison Group 1) As similar as possible with respect to other factors that could influence outcome. 2) Comparable & accurate information. Where does the comparison group come from? Ideally, from within the cohort (internal controls), but this is not always possible.

Problems with the Comparison Group Subjects may switch exposure status or become lost to

Problems with the Comparison Group Subjects may switch exposure status or become lost to follow up (quit) An Open Cohort Employees of tire manufacturer Had factor Didn’t have factor Tire makers Clerical staff Compare Incidence of Death Start of Study Past What are the strengths and weaknesses of using clerical employees as the comparison group?

Problems with the Comparison Group Subjects may switch exposure status or become lost to

Problems with the Comparison Group Subjects may switch exposure status or become lost to follow up (quit) An Open Cohort Employees of tire manufacturer Had factor Didn’t have factor Tire makers Clerical staff Compare Incidence of Death Start of Study Past The clerical staff may be much less exposed to the chemicals, but there may be important differences in confounding factors such as gender, age, socioeconomic status, education, diet, smoking, alcohol consumption, etc.

Internal Control Group Heaviest Incidence of heart disease? Nurses Leanest The best comparison group

Internal Control Group Heaviest Incidence of heart disease? Nurses Leanest The best comparison group is an unexposed or “least exposed” subset of the study cohort.

General Population Control General Population The general population is often used in occupational studies

General Population Control General Population The general population is often used in occupational studies of mortality, since data is readily available, and they are mostly unexposed. Some data sets allow adjustment for age, gender, SES, and race. vs. Rubber Workers Mortality Rates? The main disadvantage is bias by the “healthy worker effect. ” The employed work force (mostly healthy) generally has lower rates of mortality and disease than the general population (with healthy & ill people).

A Comparison Cohort Rayon Exposed Factory to disulfide Workers No disulfide exposure Incidence of

A Comparison Cohort Rayon Exposed Factory to disulfide Workers No disulfide exposure Incidence of vs. heart disease? Paper Mill Workers Both groups consist of blue collar workers, minimizing differences in SES, education, etc. The “healthy worker effect” is also not a factor. However, the paper mill workers may have other exposures that affect heart disease.

A strength is that cohort studies are efficient for unusual exposures. • Suspicion that

A strength is that cohort studies are efficient for unusual exposures. • Suspicion that occupational exposure to chemicals in tire manufacturing increase risk of death. • Viet Nam veterans with a variety of health problems. Was Agent Orange responsible? • Does x-ray treatment of ankylosing spondylitis (back problem) increase the risk of cancer? • The need for a better understanding of behavior modifications that can prevent cancer & heart disease (e. g. , smoking & obesity). However, cohort studies also provide high quality information for examining common exposures as well.

Bias From Loss To Follow-up If subjects in one of the exposure groups are

Bias From Loss To Follow-up If subjects in one of the exposure groups are more likely to be lost to follow up if they develop the outcome, then the estimate of association will be biased. OC Users Example: True incidence of thromboembolism: 20/10, 000 Subjects lost to follow up: Subjects with TE lost to follow up: Apparent incidence of TE: True RR = 2. 0 Non-OC users 10/10, 000 4, 012 4, 008 12 8/5, 988 2 8/5, 992 Apparent RR = 1. 0 Can occur in cohort studies & intervention trials. Effects: over- or under- estimate of association.

Maintain Follow Up • • • Choose subjects who are motivated Choose subjects who

Maintain Follow Up • • • Choose subjects who are motivated Choose subjects who are easy to track (professionals) Keep them interested: newsletters, incentives, part of the “family” Frequent phone calls Make questionnaires easy to fill out

Both Retrospective & Prospective: Advantages of Cohort Studies: • • Temporal sequence between exposure

Both Retrospective & Prospective: Advantages of Cohort Studies: • • Temporal sequence between exposure & disease is clear (e. g. , obesity preceded CHD) Can directly calculate incidence, RR, RD, AR% Efficient for looking at rare exposures or unusual risk factors (e. g. agent orange). Can evaluate multiple effects of a single exposure. Retrospective cohort studies: • Efficient for diseases with long latent period (time from exposure to development of disease). Prospective cohort studies: • Provide better information on exposures. • Are less vulnerable to bias because exposure status is determined before outcomes.

Enroll non-diseased subjects; collect baseline exposure data Obese Follow up at intervals to get

Enroll non-diseased subjects; collect baseline exposure data Obese Follow up at intervals to get accurate outcome data. Lean Compare incidence over time X X • Better information on exposures. • Less vulnerable to bias because exposure status is determined before outcomes. Exposed Not Exposed Identify a cohort retrospectively (e. g. tire manufacturing workers vs. desk employees. Look at what subsequently happened to them. Compare incidence X X X • Efficient. Xwith long latent period from exposure to development of disease).

Disadvantages of Cohort Studies • Inefficient for rare outcomes (both). Retrospective Cohort Study •

Disadvantages of Cohort Studies • Inefficient for rare outcomes (both). Retrospective Cohort Study • Poor information on exposures & confounding factors. • More vulnerable to bias. Prospective Cohort Study • May need large numbers of subjects for long periods of time. • Can be expensive and time consuming. • Inefficient for diseases with long latent periods. • Loss to follow up can bias results.

Enroll non-diseased subjects; collect baseline exposure data Obese Follow up at intervals to get

Enroll non-diseased subjects; collect baseline exposure data Obese Follow up at intervals to get accurate outcome data. Lean Compare incidence over time X X • Expensive and time consuming. • Inefficient for diseases with long latency. • Loss to follow up can bias results. Exposed Not Exposed Identify a cohort retrospectively (e. g. tire manufacturing workers vs. desk employees. Look at what subsequently happened to them. X X X • Poor information on exposures & X confounding factors. Compare incidence • More vulnerable to bias.

When reading a cohort study, consider… • How were the study groups selected or

When reading a cohort study, consider… • How were the study groups selected or defined? • Did they differ in other ways that could affect the outcome? • Data collection: Ø Accurate? Ø Comparable for all groups? • How complete was the follow-up?