Analytical Studies Case – Control Studies By Dr. Sameh Zaytoun (MBBch, DPH, DM, FRCP(Manch), DTM&H(UK),Dr.PH) University of Alexandria - Egypt Consultant of Preventive Medicine Al- Hada Armed Forces Hospital

Analytical Studies Cohort Natural History Case – Control Risk Factors (Exposure) Risk Factors (Exposure) Disease (Outcome) Disease (Outcome) Retrospective Prospective

Case – Control Studies  Most commonly used Epidemiologic study design despite numerous potential biases  Most suitable for diseases for which medical care is usually sought  Most suitable for diseases with relatively short period between appearance of symptoms and time of diagnosis.

Case – Control Studies More efficient than the equivalent Cohort studies Makes it possible to study Rare Diseases

Case – Control Studies Design in Words: *Select representative persons (Cases) with the study Outcome *Select comparable (Controls) without the study Outcome *Look historically in both groups for the Exposure *Compare Odds of exposure in cases and in controls (generate Odds Ratio to see if the Exposure is related to the development of the Outcome).

Interpretation of Case – Control study  All else being equal, if the Odds of Exposure differ between the Cases and the Controls by more than chance variation, the Exposure is said to be related to the Outcome

Ideal Design of a Case – Control Studies Reference Population Cases Controls A like except for case status Exposure Present Exposure Absent Identify all Exposure without Bias Exposure Present

Analysis of Case – Control Ideal Design Outcome +ve Outcome -ve Factor +veAB Factor -veCD OddsA / CB / D A / C B / D Odds Ratio = Strength of Association Outcome Present Outcome Absent Factor Present Factor Absent Factor Present Factor Absent

Rare Disease Assumption: Odds ratio ~ = Relative risk  When the disease is Rare, the exposure Odds Ratio from a case – Control study is approximately equal to the Relative Risk that would be obtained from the equivalent Cohort study.

Issues to be in concern in a Case – Control study design:  Selection of Cases  Selection of Controls ****  Ascertainment of Exposure

Selection of Cases: Often selected among persons seeking medical care A uniform diagnostic criteria to define a case is required Incident cases (versus prevalent cases) almost always preferable.

Prevalent Cases: JOver representation of cases with long disease duration (those who did not die and those who did not cured) JExposure / Disease relation may actually be an Exposure / Duration relation JSubjects less likely to remember Exposures JMore difficult to establish timing of Exposures relative to the disease onset.

Incident Cases:  Usually based on time of Diagnosis  For some diseases, onset may be long before diagnosis  Reference period for measurement of Exposure should precede the disease onset (Exposure always precedes the onset of disease i.e. there is a temporal relation).

Selection of Controls: Appropriate Source:  Hospital Controls  Neighborhood Controls  Friendship Controls  Community Controls  Multiple Control groups Inappropriate Source:  Volunteers  Groups Biased due to Exposure (e.g. GIT patients as controls in a study linking Coffee and Pancreatic Carcinoma).

Selection of Controls:  Most difficult and controversial issue in design of a Case – control study  The Controls should be an unbiased sample of the study base  Study base: source population from which cases arise during the time period when they are eligible to become cases.  Cases and controls idealy are to be taken from the same population pool.

Selection of Controls:  Controls are not selected because they have characteristic similar to the cases  Controls are selected because they would have become cases if they had gotten the disease.

Population – based Controls:  If cases consist of all individuals developing the disease in a defined population, the best control group is a random sample of individuals from the same source population who have not developed the disease.  It also could be taken through a random digit dialing or through population registries (e.g. census, health insurance….etc).

Clinical Controls: [Patients seeking care for conditions other than the disease of interest at the facilities where the cases are identified [Best to choose patients with a variety of diseases [Patients with diseases thought to be related to the Exposure of interest should be excluded.

Clinical Controls:  Certain Exposures (e.g smoking, obesity) are over represented among hospital Controls because these Exposures are associated with many different diseases

Neighborhood Controls:  Assumes that neighbors of cases would seek care at the same medical facility as the cases.  May not be possible to examine risk factors that are closely linked to Socio-economic or Environmental exposures, because cases and controls are too similar.

Selection of Controls:  In some situations, no single Control group is obviously the best  May include two or more control groups (e.g. population controls and clinical controls).

Obtaining Exposure information:  Interview  Existing records  Physical measurements  Laboratory tests

Obtaining Exposure information:  Methods must be comparable in Cases and in Controls  Observers should be “blind” to Case / Control status  Appropriate definition of Reference period is essential  How define Reference period for Controls?

Obtaining Exposure information:  Definition of Reference period should be based on knowledge about the disease in question  For chronic disease with long latent period, reference period may be very long  For acute disease, reference period may be a short period immediately preceding the diagnosis.

Advantages of Case – Control studies:  Fewer subjects required than the Cohort studies  Less expensive and faster than Cohort studies  Possible to study Rare diseases  More than one Risk factor can be studied at the same time.

Disadvantages of Case – Control studies: The events of interest have already occurred when the study is done Exposure information may not be available or may not be accurate Prone to recall bias Prone to selection bias Relative risk (Risk Ratio) of the disease can not be estimated (it could only estimate the Odds ratio).

Preventive Medicine Department 2007