Study Designs

observational studies

Objectives
Define and understand design issues relating to cohort studies Understand concepts including: selection of the cohort, defining the population at risk, measurement of exposure, outcome status and types of cohort data

Incidence of Diabetes Among Dependents of the U.S. Military Forces Admitted to U.S. Army Treatment Facilities, 1971-1991

Objective
To determine the national incidence of diabetes in children by studying a group representing all parts of the country: the dependent children of U.S. Military personnel.

Incidence of Diabetes Among Dependents of the U.S. Military Forces Admitted to U.S. Army Treatment Facilities, 1971-1991

Research Design and Methods

Dates of admission, diagnosis of diabetes, age, and gender were collected for all 522,326 children age 21 or younger, of active duty military personnel admitted to US Army treatment facilitated during fiscal years 1971-1991. Incidence rates were expressed as cases per 100,000 person-years.

Incidence of Diabetes Among Dependents of the U.S. Military Forces Admitted to U.S. Army Treatment Facilities, 1971-1991

Results A total of 2308 cases of diabetes were diagnosed in 14.3 million person-years of follow-up over the 21 years. The overall incidence rate of diabetes in this population is 16.2 (95% CI 15.5 16.91) For 1987-1991, the age-specific rates were 8.1 (0-4 years), 15.9 (59 years, 25.6 (10-14 years), 23.9 (15-19 yrs), and 23.4 (20-21 years)

Conclusion ?????

Major Types of Observational Research Designs / purpose of each:

Cohort
Analytic / descriptive

Case-Control
Cross-Sectional

Analytic

Descriptive / hypothesis generating

note: we will also discuss hybrid designs

Epidemiologic definition of cohort

Chort: A group of individuals that share a common characteristic Example:
Birth cohort: individuals born in the same period (often year) Exposure cohort: individuals sharing a common exposure (often an occupational exposure such as asbestos, etc.)

Definition of a cohort study

The observation of a cohort(s) over time to measure a stated outcome. Two primary purposes
Descriptive (measures of frequency)
To describe the incidence of an outcome over time or to describe the natural history of disease

Analytic (measures of association)

To analyze the relation between occurrence of outcomes and risk factors (or predictive factors)

Cohort Studies: distinguishing features

Directionality: forward, incident cases E PAR E D / D D/ D
PAR = population at risk

Cohort Studies
(prospective, longitudinal)
Usually undertaken when: sufficient evidence has accumulated from other studies to indicate a prospective cohort study is warranted a new agent is introduced and requires monitoring for its possible association with adverse health outcomes (levaquin, vioxx) temporal association is unclear from a case-control study impressive results are obtained from a c-c study (either positive or negative) and issues of validity (selection or information bias) are evident or are a concern

Is Mold Exposure a Risk Factor for Asthma?

A remarkably consistent association between home dampness and respiratory symptoms and asthma has been observed in a large number of studies conducted across many geographic regions . In a recent review of 61 studies, it was concluded that dampness was a significant risk factor for airway effects such as cough, wheeze, and asthma, with odds ratios ranging from 1.4 to 2.2. Positive associations have been shown in infants, children, and adults, and some evidence for dose-response relations has also been demonstrated .

Is Mold Exposure a Risk Factor for Asthma?

Although it has been concluded that the evidence for a causal association between dampness and respiratory morbidity is strong, this evidence is based mainly on cross-sectional studies and
prevalence case-control studies; few prospective studies have been conducted

Cohort Study
Major Concerns
Selecting a cohort (sampling frame, sampling and recruitment, external vs internal validity)
Please read Delnevo et al paper posted on BB

Exposure assessment Follow-up

Selecting a Cohort
Population Based Cohort Studies

Population Subgroup Cohort Studies

Selecting the Cohort

Population Based Cohort Studies Any well-defined population (geographic,
occupational, membership in HMOs)

Typically evaluate multiple hypotheses Primary Justification :

external validity

 Example: Nurses Health Study

Begun in 1976 ~ 270 published papers Original study question = oral contraceptives and breast cancer Many other areas researched

Cohort
Married registered nurses Between ages 30-55 (in 1976) Living in 11 most populous states whose nursing boards agreed to supply members names 122,000 out of 170,000 responded Follow-up to date: 90%

Thoughts?

 Example: Nurses Health Study II

Begun in 1989 Original study question: oral contraceptives, diet and lifestyle risk factors in a younger cohort Planned to collect better exposure information (type of OC, duration, important covariates)

Cohort
Registered nurses, 25-42 years, Sample size = 125,000 Recruitment: send a single questionnaire. Enroll all eligible who respond 116,686 out of 517,000 enrolled Follow-up to date: 90%

Thoughts?

 Example: Nurses Health Study III

Currently enrolling Female RNs and LPNs age 22-42 from around the country. Research question: how new hormone preparations, dietary patterns and nursing occupational exposures impact womans health. An invitational mailing sent to ~ 1 million nurses.

Thoughts?

Selecting the Cohort, contd

Population Based Cohort Studies Advantages
Estimation of distribution and prevalence of relevant exposure variables Calculation of risk factor trends over time Strong internal validity Strong external validity (primary justification)

Disadvantages
Expensive, logistically complicated Often associated with large loss to follow-up If exposure is rare, inefficient

Selecting the Cohort, contd

Sampling Frame
Total population Probability samples of the population

The extent to which a cohort sample is representative of the total reference population depends on the completeness of the population frame available to sample from as well as participation rates.
please refer to Delnevo et al article as an example.

Similar to the concept of the source population

Selecting the Cohort, contd

Population Based Cohort Studies :
External Validity Issues and Considerations

Depends on eligibility criteria for inclusion Initial response of the sample Stability of the cohort on follow-up. Requires variability of exposure and outcome levels Susceptibility of the population to the risk factor

Selecting the Cohort, contd

Example of the importance :
Have smokings risk been underestimated by US cohort studies that exclude the poor. Presented at APHA, November 2000. Source of smoking risk data based on nurses, Cancer Society or MRFIT volunteers, HMO members. - What do you think of the cohort??

Selecting the Cohort, contd

Population Subgroups: special/exposed groups
May ensure the cohort has exposure of interest Less likely to be lost to follow-up because of lower mobility (military, occupational cohort) May have relevant information on exposure & potential confounders in the medical and employment records Reduced ability to generalize results to the general population Access to data may be limited Generally, smaller sample sized needed

Selecting the Cohort: The non-exposed

internal comparison groups: select from the same source population as Exposed
increases the likelihood that the E and E members are from a similar subgroup of the population
generally have the same follow-up procedures and therefore, the same likelihood that D will be detected

Selecting the Cohort: The non-exposed

external comparison groups: chosen from a different source population
often general population controls from area are used

must be susceptible to the same selective factors as the E group less costly if data already available sometimes called SMR studies

Selecting the Cohort, contd

Levels of subject selection: Target Population: population to which results can be applied Source Population: the population, defined in general terms and enumerated if possible, from which eligible subjects are drawn

Eligible Population: the population of subjects eligible to participate Study Participants: those people you contribute data to the study

Exposure: important issues

Definition of exposure: intensity, duration Induction period Latency Changing exposures Allocation of person-time in the above examples Categorizing exposure

Exposure: important issues

Induction period
Duration of time that it takes from exposre to onset of disease Time during which exposure occurs time at risk Example: radiation exposure and leukemia, ~3.5 years.
Exposure is classified as high, medium and low based on the amount of time working in a job where you are exposed to radiation PT at risk. What do you do with the person-time that accrues prior to the induction time? Only include time at risk of the outcome in the denominator of the rate.

Exposure: important issues

Latency period
Duration of time from disease initiation to disease detection. Very relevant when considering covariates such as detection bias, etc

Exposure: important issues

Changing exposures:
Calculation of rates (as opposed to risks) allows flexibility in the analysis of cohort data. An individual can contribute follow-up to several different exposure-specific rates, depending on details of the study hypothesis The definition of the exposure group corresponds to the definition of PT eligible for each level of exposure.

How to handle changing exposures depends also on cross over effects. If the effect of being exposed is cumulative, you can not change exposure groups when exposure ceases.

Exposure: important issues

Categorizing exposures
Often there is no guidance on appropriate categories of exposure. Or the line between exposed and unexposed is not defined No problem if your data are continuous If you want to calculate rates directly, you must observe populations within categories of exposure. Common error: apportioning to PT time, the unexposed time of a person who eventually becomes exposed.
Occupational study where exposure is categorized according to duration of employment in a particular job. Highest exposure category is at least 20 years of employment. If a worker has been employed 30 years, it is a mistake to assign that employee to the 20+ years of employment because they only reached that exposure in the last 10 years. Thats the time frame relevant to 20+ years of exposure.

Exposure: another issue, measurement

Is Mold Exposure a Risk Factor for Asthma?:
It is not clear whether molds are merely markers of dampness or are causally related to the symptoms associated with dampness. Assessment of exposure to molds is often done by questionnaire. It is unknown to what extent questionnaire reports of mold growth correlate with exposure to relevant mold components .

Exposure: measurement, an example

Is Mold Exposure a Risk Factor for Asthma?:
If mold exposure is quantified Perhaps the most important problem, one that has rarely been acknowledged in the studies published to date, is that air sampling for mold for than 15 minutes is often impossible, and air concentrations usually vary a great deal over time. The few studies that have included repeated exposure measurements of mold have shown considerable temporal variation in concentrations, even over very short periods of time. Variability in isolated genera was even more substantial.

The Duration and Timing of Exposure: Effects of Socioeconomic Environment on Adult Health (AM J Public Health, 1999;89:1059-1065)

Objectives: This study investigated timing and duration effects of SES on self-rated health at 33 yrs of age and established whether health risks are modified by changing SES and whether cumulative SES operated through education.

The Duration and Timing of Exposure: Effects of Socioeconomic Environment on Adult Health (AM J Public Health, 1999;89:1059-1065)

Methods: Data were from the 1958 British birth cohort. Occupational class at birth and at 16, 23, and 33 years of age was used to generate a lifetime SES score.

The Duration and Timing of Exposure: Effects of Socioeconomic Environment on Adult Health (AM J Public Health, 1999;89:1059-1065)

Results:
At 33 yrs of age, 12% of men and women reported poor health. SES at birth and at 16, 23 and 33 years of age was significantly associated with poor health for all ages. No large differences in effect sizes emerged, suggesting that timing was not a major factor. Odds of poor health increased by 15% (men) and 18% (women) with a 1-unit increase in the lifetime SES score. Strong effects of lifetime SES persisted after adjustment for education level.

Follow-up
Systematic, standardized data collection procedures on all or a sample of cohort members regardless of exposure status to avoid surveillance bias. Data collection relies on primary and secondary collection procedures - linking of established dbf; professional, government, etc Controlling loss to follow-up is key.

- baseline recruitment strategy; key identifiers for searching,

adequate info to analyze differences in participation rates. Downside - longer questionnaire, interview may inhibit recruitment - mail, telephone survey, - both, monetary incentives, etc.

Loss to Follow-up
Major portion of staff efforts are toward reducing loss to follow-up. Ways to reduce loss to follow-up ??

Types of Cohort Studies

Concurrent Retrospective Mixed Design

COHORT STUDIES
Advantages:
Study many different outcomes with exposure of interest Temporal relation not in doubt, therefore, preferred for causal inference Less prone to selection bias as D status does not influence selection of subjects with respect to exposure Repeated exposure data can be collected Provides information on changing risks over time Modification of risks by increasing age

COHORT STUDIES
Disadvantages:

Costly, resource intensive (manpower, time and money) Loss to follow-up of study subjects Inefficient for studying diseases with long latency Inefficient for studying rare diseases
- example : If ID = 5 per 100,000 per year and sample size calculations say you need 100 cases, given an initial cohort of 40,000 subjects follow-up would have to continue for 50 years Study effects

Changing exposure Withdrawals/loss to follow-up Basic design allows only 1 risk factor to be studied