Case-Control studySelection of Cases

• Diagnostic criteria: specific to each investigation; homogeneous group of cases

• The source of cases: primary study base secondary or case-defined study base

• Incident or prevalent case

Case-Control studyPrinciples, control selection

• Should be selected from the samepopulation that gave rise to the cases

• Controls should be selected independently of their exposure status; If sampling rate, the same for exposed and unexposed, is known, incidence rate can be calculated

Case-Control studySelection of Controls

• Sources 1: a population explicitly defined

• Methods:

1. No sampling: total population

2. Random and systematic sampling

3. Paired sampling

CasCase-Control study

• When a list of all potential controls is not available1. Random digit dialing (RDD) Sampling of households based on random selection of telephone numbers; matched to cases on area code and prefix

2. Paired Sampling Primary or *Secondary study baseAlternative to RDD or RDD not realisticImplicit, indirect matching

Case-Control studyPaired sampling

Objective• to provide a sampling scheme for control selection

that minimizes subjectivity and arbitrariness during the process Individuals are selected by virtue of some defined temporal or geographic relationship to the case

Example: • Next patient admitted after the case, the person

living in the nearest residence to that of case, the student next to the case in an alphabetical class listing

Case-Control studyMatching; pre-specified distribution

• Explicitly identified matching variables and values

• Paired sampling: the next person admitted who satisfied the defined criteria

• To select controls identical to the cases with respect to one or more potentially confounding factors, with certain homogeneous levels

Confounding

• Rates: Counterfactual

Substitution/Reference group

• If both rates are not equal, before-after rate difference is confounded for the causal rate difference or ratio

Confoundingdefinition

• A distortion of an exposure-outcome association brought about by the association of another factor with both outcome and exposure.

• The definition of confounding involves a definition of the study hypothesis

• Two associations, One condition

Criteria for a confounding facCriteria for a confounding factor

• A confounding factor must be a risk factor for the disease: must be predictive of disease occurrence apart from its association from exposure

• i.e. predictive among unexposed or reference group

Criteria for a confounding facCriteria for a confounding factor

2. A confounding factor must be associated with the exposure under study in the source population (the population at risk from which the cases derived)

3. A confounding factor must not be affected by the exposure or the disease Cannot be an intermediate step in the causal pathway Should be an extraneous risk factor

Standardization1

*StandardThe set of weight that is used to taking weight

average

**Standardized Adjustment has been made for the effects of one or more potential confounding factors by calculating a weighted average of category-specific rates

Standardization

• Direct

a standard population with a known age distribution is selected comparable, a directly standardized rate can be compared with any other rate standardized to the same population

• Indirect

a set of age-specific standard rates is selected

StandardizaStandardizationStandardized Mortality Ratio; SMR

• Indirect, Rates from:

1. non-exposed group from within the same occupational setting

2. A general population, e.g., TW male aged 20-59 years

• Standardized mortality ratio = O/E

SMR

• O: the number of cases observed in the study group

• E = T1I1*+T2I2* +------

• It is generally not equal to the number of cases one should expect in the study group if it had experienced the rates of the reference population; Alteration of the person-time rate usually alters the distribution of person-time in the study group

*Assumption:

SMR• Excess risk among those exposed

• Using general population as standard, the magnitude is less than what has been estimated by relative risk; underestimate the increased or decreased risk

• Should not be directly compared to evaluate the relative effect of different levels of exposure

• The only valid comparison of an indirectly standardized rate is with the population from which the standardized rates derived

Causal relationship

• Study design, selection of study subjects: external validity to be reasonable

• Do the results support a causal relationship?

• Observation bias confounding chance causal relationship Fall 2006 NCKU

Observation bias

• Relevant to the measurement of the dependent variable in the study

• In a cohort study: outcome

• In a case-control study: exposure

• The key issue is the relationship between the true value of the factor being assessed and the value of the variable chosen to represent the factor in the study

Non-differential error/bias

• All methods of measurement will have a degree of error which is a function of the measurement used

• However, the inaccuracy is similar in the different groups of subjects being compared

The effect of non-differential error

• Make the observed association, e.g., the relative risk estimate, closer to the null value that is the true situation

• The exposure variable measured, a very inaccurate estimate of the true biological factor concerned, because it is an extremely indirect measurement

• The closer we come to the biological causal factor, the higher the relative risk will become

• e.g., smoking: Yes/No, package-yr, DNA adduct

Bias, differential

• Inaccuracy which is different in size or direction in one of the groups under study than in others

• The effect: bias can influence the results of a study in any direction

• The most important sources of bias are variation in the subject’s response to the method of assessment, and variation in the observer’s response

Bias in case-control study1Selection

• Selection bias can occur whenever the inclusion of cases or controls into the study depends in some way on the exposure of interest, since exposure and disease have both occurred

• e.g., Milk drinking and Salmonella infection