RACE 612 Study Designs & Measurements Assoc.Prof.Dr.Atiporn Ingsathit Assoc.Prof.Dr.Patarawan Woratanarat Dr.Sakda Arj-ong Vallipakorn Dr.Pawin Numthavaj

Semester 1 Academic year 2015

Doctor of Philosophy Program in Clinical Epidemiology, Master of Science Program in Medical Epidemiology Section for Clinical Epidemiology & Biostatistics Faculty of Medicine Ramathibodi Hospital, Mahidol University

CONTENTS Cohort studies ..................................................................................................... 3 Cohort population................................................................................................ 3 When should we use cohort design?.................................................................. 5 Type of cohort studies......................................................................................... 6 Advantages and disadvantages of cohort studies............................................. 8 What to look for in cohort studies? ...................................................................... 9 Way to express and compare risk .................................................................... 11 How to calculate the risks? ............................................................................... 12 Confounding ...................................................................................................... 13 Summary ........................................................................................................... 14

OBJECTIVES 1) Able to describe definition of cohorts and studies of risk 2) Able to discuss definition, classification advantages and disadvantages of cohort studies 3) Able express and compare risk 4) Able to discuss and control confounding factors

REFERENCE 1. Fletcher RH. Clinical Epidemiology the Essentials 5th Edition: Chapter 5 Risk : Exposure to Disease. Lippincott Williams & Wilkins. 2014; 61-77 2. Rothman K. Modern epidemiology. Section II, Chapter 7: Cohort Studies 3rd ed. Lippincott Williams & Wilkins. 2008;100-110

SUGGESTED READING Grimes DA, Schulz KF. Cohort studies: marching towards outcomes. Lancet. 2002;359(9303):341-5. Appendix II: Song JW, Chung KC. Observational studies: cohort and case-control studies. Plastic and reconstructive surgery. 2010;126(6):2234-42. Appendix III: Winner B, Peipert JF, Zhao Q, Buckel C, Madden T, Allsworth JE, et al. Effectiveness of long-acting reversible contraception. The New England journal of medicine. 2012;366(21):1998-2007. Appendix I:

ASSIGNMENT III: Cohort study (15%) P. 15, Due date: 14th September 2015 2|Page

COHORT STUDIES Cohort study is an analytical type of observational study, based on usually primary data, from a follow-up period of a group in which some have had, have or may have the exposure of interest, to determine the association between that exposure and an outcome. It is the highest in hierarchy of evidence in terms of observational studies, but it cannot provide empirical evidence that is as strong as that provided by properly executed randomized controlled clinical trials.

COHORT POPULATION The term “cohort” is derived from the Roman word cohort. During battle each cohort, or military unit, consisted of a specific number of soldiers and were traceable. The word “cohort” has been adopted into epidemiology to define a set of people followed over a period of time. W.H. Frost, an epidemiologist, was the first to use the word “cohort” in his 1935 publication assessing age-specific mortality rates and tuberculosis. The modern epidemiological definition of the word now means a “group of people with defined characteristics who are followed up to determine incidence of, or mortality from, some specific disease, all causes of death, or some other outcome. Focusing on follow-up period or person-time, we can categorize a cohort population into 2 groups based on the movement of individuals in a cohort. First, fixed or closed cohort is determined when there is no movement of individuals between exposure groups during the follow-up. Second, opened or dynamic cohort describes a population which can be assembled from a changing registration of individuals.

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The main key element of cohort study is to track two or more groups forward from exposure to outcome. Figure 2 illustrates the study design. Researchers select subjects at the onset of the study and then determine whether they have the risk factor or have been exposed. Then all subjects are followed up over a certain period of time to observe the outcome or the effect of the risk factor or exposure. Most importantly, all subjects must not have the outcome of interest at the origin. Figure 1. Diagram of cohort study design

Exposed

With outcome

Without outcome With outcome Non-exposed

Without outcome Time

Direction of study

Cohort study

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WHEN SHOULD WE USE COHORT DESIGN? Many research questions can be answered by observational studies especially the risk question which cannot be studied with experimental studies. It is usually not possible to conduct an experiment because it would be unethical to introduce possible risk factors on a group of healthy people. Research questions which cohort studies can be used for have been demonstrated in Table 1.

Table 1. Cohorts and their purposes Characteristic in common

To assess effect of

Example

Exposure

Risk factor

Lung cancer in people who smoke

Disease

Prognosis

Preventive intervention

Prevention

Survival rate for patients with breast cancer Reduction in incidence of pneumonia after pneumococcal vaccination

Therapeutic intervention

Treatment

Improvement in survival for patients with Hodgkin’s disease given chemotherapy

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TYPE OF COHORT STUDIES Cohort studies can be conducted in 2 types 1. Prospective cohort studies or concurrent cohort studies This cohort can be assembled in the present and followed into the future. When the study is planned before collecting data, researchers can be sure to collect all variables including possible confounders. In a prospective study, the investigator begins the study at the same time as the first determination of exposure status of the cohort. When proposing a prospective cohort study, the investigator first identifies the characteristics of the group of people he/she wishes to study. The investigator then determines the present case status of individuals, selecting only non-cases to follow forward in time. Exposure status is determined at the beginning of the study. All information in a prospective cohort study can be collected in a standardized method that reduces measurement bias. 2. Retrospective cohort studies or historical cohort studies This cohort can be identified from past records and followed from that time up to the present. It takes advantage of well-designed medical databases. It can take less time to outcome development. However, some factors may not have been recorded, so they cannot be included in the analysis, which means confounders may not be controlled. Doing a retrospective cohort study requires sound data on exposure status for both cases and noncases at a designated earlier time point.

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Quiz: How does a retrospective cohort study differ from a casecontrol study? Suppose you are investigating the association of caffeine consumption and bone loss among lecturers at a university. How would the sample selected for a case-control study differ from those included in a retrospective cohort study?

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ADVANTAGES AND DISADVANTAGES OF COHORT STUDIES The strengths and limitations of different types of cohort studies have been summarized in Table 2. Table 2. Advantages and disadvantages of cohort studies

Advantages All cohort study types  The only way to estimate incidence  Follows the same logic as the clinical question  Demonstrates temporal relationship  Exposure can be identified without bias of knowing the outcome  Can assess the relationship between exposure and many disease Prospective cohort studies  Can collect lifestyle and demographic data not available in most medical records  Can set up standardized methods of measuring exposure and outcomes Retrospective cohort studies  More efficient; faster, cheaper, less man power needed because data has already been collected

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Disadvantages o Susceptible to confounding and other biases

o Expensive and inefficient because many subjects must be enrolled and follow-up over time o Cannot be used for rare disease

o Range of possible risk factors is narrower than prospective design o Cannot examine patient characteristics not available in the data set used o Measurement may not be standardized

WHAT TO LOOK FOR IN COHORT STUDIES? Who is at risk? All participants (both exposed and unexposed) in a cohort study must be at risk of developing the outcome. For example, since women who have had a tubal sterilization operation have almost no risk of salpingitis, they should not be included in cohort studies of pelvic inflammatory disease.

Who is exposed? Cohort studies need a clear, unambiguous definition of the exposure at the outset. This definition sometimes involves quantifying the exposure by degree, rather than just yes or no. For example, the minimum exposure might have to be 14 cigarettes per day or less, or 3–6 months of steroid use.

Who is an appropriate control? The key notion is that controls (the unexposed) should be similar to the exposed in all important respects, except for the lack of exposure. If so, the unexposed group will reveal the background rate of the outcome in the community. The unexposed group can come from either internal (persons from the same time and place, such as a hospital ward) or external sources. Internal comparisons are most desirable.

Have outcomes been assessed equally? Outcomes must be defined in advance, and they should be clear, specific, and measurable. Identification of outcomes should be comparable in every way for the exposed and unexposed to avoid information bias. Keeping those who judge outcomes unaware of the exposure status of participants (blinding) in a cohort study is important for subjective outcomes, such as pain or erythema. By contrast, with objective outcome measures, such as death, blinding the exposure status is less important. 9|Page

Have losses been minimized? Although loss of participants damages the power and precision of a study, differential loss to follow-up is more threatening. If the likelihood of drop out is related both to exposure and outcome, then bias can result. For example, some participants given a new antibiotic might have such poor outcomes that they are unable to complete questionnaires or to return for examination. Their disappearance from the cohort would make the new antibiotic look better than it is. The best way of dealing with loss to follow-up is to avoid it. For example, restrict participation to only those judged likely to complete the study.

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WAY TO EXPRESS AND COMPARE RISK A cohort study is useful for estimating the risk of disease. Absolute risk is the probability that people who are exposed to certain “risk factors” will subsequently develop a particular disease more often than similar people who are not exposed. Its value is the same as that for incidence and the terms are often used interchangeably. Table 3 demonstrates ways to express and compare risk in a cohort study.

Table 3. Ways to express and compare risk Expression Absolute risk

Question group initially free of the condition?

Definition I = #new case #People in group

Attributable risk (Risk difference)

What is the incidence of disease

AR = IE+-IE-

Relative risk (Risk ratio)

How many times more likely are exposed RR = IE+/ IE-

What is the incidence of disease in a

attributable to exposure? persons to become diseased, relative to nonexposed persons?

Populationattributable risk

What is the incidence of disease in a

ARp = AR x P

population, associated with the

(P=prevalence of

prevalence of a risk factor?

exposure)

PopulationAFp = ARp/IT What fraction of the disease in a attributable fraction population is attributable to exposure to a (IT = Total incidence of disease in a population) risk a risk factor?

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HOW TO CALCULATE THE RISKS? Formulas and examples for calculating risks in cohort studies have been demonstrated in Figure 2. Figure 2. Example for risk calculation 1

Way to express and compare risk Expo sure

Disease

No disease

Total

Stone

CKD

No CKD

Total

+

a

b

a+b

Yes

80

10

90

-

c

d

c+d

NO

20

90

110

b+d

n

100

200

a+c Term Risk

Relative risk

100

General

Example

Question?

a/(a+b) Or c/(c+d)

80/90 Or 20/110

What is the incidence of disease in a group initially free of the condition?

a/(a+b)  c/(c+d)

80/90  20/110 =5

How many times more likely are exposed persons to become disease, relative to nonexposed persons?

Figure 3. Example for risk calculation 2

Way to express and compare risk Expo sure

Disease

No disease

Total

Stone

CKD

No CKD

+

a

b

a+b

Yes

80

10

90

-

c

d

c+d

NO

20

90

110

b+d

n

100

200

a+c Term Attributable risk (AR) Population attributable risk PAR= ARxPEX

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100

Total

General

Example

Definition

a/(a+b) – c/(c+d)

80/90 – 20/110 = 0.7

The incidence of disease attributable to exposure

AR x (a+b)/n

0.7 x 90/200 = 0.32

The incidence of disease in a population is associated with the occurrence of a risk factor

CONFOUNDING A confounding factor is one that is: 1. Associated with exposure and its distribution between exposure and nonexposure is not similar 2. Associated with disease 3. Not part of the causal chain from exposure to disease Mostly risk studies are conducted by observational studies which cannot threaten the internal validity by confounding factors. To determine whether a factor is independently related to risk, we have to control the potential confounders. There are several possible ways of controlling for the different confounders between groups. Table 4. Methods for controlling confounding Method

Description

Phase of study Design

Randomization

Assign patients to groups in a way that

Analysis

+

gives each patient an equal chance of allocating into one or the other group Restriction

Limit the range of characteristics of

+

patients in the study Matching

For each patients in one group, select

e.g. propensity

one or more patients with the same

score matching

characteristics for a comparison group

Stratification

Compare rates within subgroups (strata)

+

+

+

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Simple adjustment Mathematically adjust crude rates for one (Standardization)

+

or a few characteristics, so that equal weight is given to strata of similar risk (commonly used for a single variable adjustment)

Multivariable

Adjust for differences in a large number

adjustment

of factors related to outcome, using

+

mathematical modeling technique

SUMMARY Cohort studies are common in medical research. Like other research designs, they have both advantages and disadvantages. Readers should make sure that investigators provide clear, measurable definitions of exposures and outcomes. The unexposed group should resemble the exposed group in all important respects, and determination of outcomes should be objective and, whenever possible, blinded. The ways to express risk is usually provided as rates, or relative risks. Reports of cohort studies should identify and describe the potential effect of biases. Importantly, investigators should measure and control for potential confounding factors.

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ASSIGNMENT III (15%) 

Due date: 14th September 2015

Assigned reading Reading the article “Everolimus-Eluting stents or bypass surgery for multivessel coronary disease” New England Journal of Medicine 2015; 372:1213-22.

Answers the following study questions, a. What was the study design (in brief)? b. What was the target population? c. What was the study population? Was there a representative sample of population? d. How they sampling the participants? e. What are the results? Please interpret the main findings. f. From Table 2, please calculate and interpret measure of association between treatment groups and outcomes. g. What were the potential biases of this study? How did the investigators cope with this bias in their analyses? h. What were the strength and weakness points in this study? i.

If you want to conduct the new study about this question in your country, what is your plan? ************************************************************************************

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