Case-Control Study - 15 Mark Exam Answer

Definition

• Both exposure and outcome (disease) have occurred before the start of the study
• The study proceeds backwards - from effect to cause
• It uses a control group to support or refute an inference

Design

Steps in Conducting a Case-Control Study

1. Selection of Cases and Controls

• Diagnostic criteria must be defined before the study (e.g., histologically confirmed cancer). These criteria must not be altered during the study.
• Eligibility criteria: Newly diagnosed (incident) cases within a specified period are preferred over prevalent/old cases, as prevalent cases may reflect survival rather than disease onset.
• Sources: Cases may be drawn from hospitals (hospital-based) or from the general population via disease registries or surveys (population-based).

• Controls must be free from the disease under study.
• They must be as similar to the cases as possible except for the absence of the disease.
• Sources of controls include: hospital patients with other conditions, general population, relatives, neighbours, or occupational groups.
• A key rule: controls should be subjects who might have been cases in the study but are selected independent of the exposure.

2. Matching

• Smoking is a confounder in a study of alcohol and oesophageal cancer (since smokers tend to drink and smoking independently causes cancer)
• Age is a confounder in a study of oral contraceptives and breast cancer

• Group (frequency) matching: Cases and controls are matched in strata so the frequency distribution of matched variables is similar in both groups.
• Individual (pair) matching: For each case, one control is selected that closely matches on chosen variables (e.g., same age, sex, occupation). Analysis of matched pairs uses McNemar's test.

3. Measurement of Exposure

• Information on past exposure must be obtained in exactly the same manner for both cases and controls.
• Methods include interviews, questionnaires, medical records, and biological specimens.
• Exposure data is collected retrospectively, which introduces the risk of recall bias.

4. Analysis and Interpretation - Odds Ratio (OR)

• a = cases exposed
• b = controls exposed
• c = cases not exposed
• d = controls not exposed

• OR = 1: No association
• OR > 1: Positive association (risk factor)
• OR < 1: Negative association (protective factor)

Bias in Case-Control Studies

Advantages of Case-Control Studies

1. Relatively easy to carry out
2. Rapid and inexpensive compared to cohort studies
3. Require few subjects
4. Particularly suited to rare diseases (e.g., leukaemia in adolescents)
5. No risk to subjects (no intervention)
6. Allows study of multiple aetiological factors simultaneously (e.g., smoking, physical activity, personality in MI)
7. Can identify risk factors to guide prevention programmes
8. No attrition problems - no follow-up required
9. Minimal ethical issues

Disadvantages

1. Prone to bias - relies on memory or past records of uncertain accuracy
2. Selection of controls is often difficult
3. Cannot measure incidence rates - only OR (estimated RR)
4. Does not easily distinguish causes from associations
5. Not suited to evaluation of therapy or prophylaxis
6. Representativeness of both cases and controls may be questionable

Classic Examples

1. Cigarette smoking and lung cancer - Doll and Hill (1950): First landmark case-control study showing a strong association between smoking and lung cancer.
2. DES and vaginal adenocarcinoma: 8 young women (15-22 years) with vaginal adenocarcinoma were compared with 32 matched controls. Seven of the 8 cases had been exposed to diethyl-stilboestrol (DES) in foetal life vs. none of the controls (p<0.00001), revealing DES as the cause 10-20 years after in utero exposure.
3. Oral contraceptives and thromboembolic disease - Vassey and Doll (1968-69): 50% of 84 women with venous thrombosis/pulmonary embolism had used oral contraceptives vs. only 14% of controls; relative risk 6.3:1.
4. Thalidomide and congenital malformations: Retrospective study of 46 mothers of deformed babies showed 41 had taken thalidomide in the first trimester.

Summary Table: Case-Control vs. Cohort Study

Epidemic - Definition and Steps of Investigation

DEFINITION OF EPIDEMIC

• Epidemicity is relative - it depends on the usual frequency of the disease in the same area, among the specified population, at the same season of the year
• The number of cases indicating an epidemic varies according to: the agent, size and type of population exposed, previous immunity, time, and place
• Even a single case of a communicable disease long absent from a population may require immediate investigation and reporting
• Two cases associated in time and place of a disease not previously recognized in an area may be sufficient to constitute an epidemic

Related Terms

OBJECTIVES OF EPIDEMIC INVESTIGATION

1. To define the magnitude of the epidemic in terms of time, place, and person
2. To determine the conditions and factors responsible for its occurrence
3. To identify the cause, source of infection, and mode of transmission to guide control measures
4. To make recommendations to prevent recurrence

STEPS OF INVESTIGATION OF AN EPIDEMIC

Step 1: Verification of Diagnosis

• A clinical examination of a sample of cases is sufficient - not every case needs examination
• Laboratory investigations (wherever applicable) are most useful to confirm the diagnosis
• Epidemiological investigations should NOT be delayed until laboratory results are available - both proceed in parallel

Step 2: Confirmation of the Existence of an Epidemic

• An epidemic is said to exist when the observed frequency exceeds the expected frequency based on past experience
• An arbitrary limit of two standard errors above endemic occurrence is used as the epidemic threshold for common diseases (e.g., influenza)
• Some epidemics are easily recognised (common-source epidemics of cholera, food poisoning, hepatitis A)
• Modern epidemics (cancer, cardiovascular diseases) may not be easily recognised without comparison to previous data

Step 3: Defining the Population at Risk

• A detailed and current map of the area must be available before investigation begins
• The map should show: natural landmarks, roads, locations of all dwelling units
• The area is divided into segments using natural landmarks as boundaries, then subdivided further

• A complete census of the population by age and sex is carried out via house-to-house visits
• Lay health workers can be employed for this purpose
• Without an appropriate denominator of "population at risk," attack rates cannot be calculated
• Attack rates help identify risk factors and subgroups most affected

Step 4: Rapid Search for All Cases and Their Characteristics

• Name, age, sex, occupation, social class, travel history
• History of previous exposure and immunity status
• Time of onset, signs and symptoms
• Personal contacts (home, work, school)
• Special events (parties attended, foods eaten, water and milk exposure)
• History of injections, blood products, or attendance at large gatherings

• Patients are asked if they know of other cases in the home, family, neighbourhood, school, or workplace with onset within the incubation period of the index case
• Hospital records are also checked
• The search for new cases continues every day until the area is declared free of the epidemic - usually for a period equal to twice the incubation period after the last case

Step 5: Data Analysis

• Prepare a chronological distribution of dates of onset - construct an "epidemic curve"
• The epidemic curve can suggest:
  • A time relationship with exposure to a suspected source
  • Whether it is a common-source (single sharp peak) or propagated (multiple successive peaks) epidemic
  • Seasonal or cyclic patterns suggesting a particular infection
• The shape of the epidemic curve helps estimate the incubation period and the likely time of exposure

• Prepare a "spot map" showing the geographic distribution of cases
• Clustering of cases in a particular area points to a localised source (e.g., contaminated water supply, food establishment)

• Analyse data by age, sex, occupation, and other risk factors
• Calculate attack rates and case fatality rates for those exposed and not exposed
• In food-borne outbreaks, food-specific attack rates must be calculated for each food eaten to identify the vehicle of infection
• The purpose is to identify the common event or experience that delineates the group involved

Step 6: Formulation of Hypotheses

1. Possible source of infection
2. Causative agent
3. Possible modes of spread
4. Environmental factors that enabled it to occur

Step 7: Testing of Hypotheses

• The hypothesis that is consistent with all known facts is retained
• When divergent theories arise, distinguish between those that are sound and those that are merely plausible by looking at evidence from the subsequent course of events
• Statistical methods (chi-square, odds ratio) may be used to test the strength of associations

Step 8: Evaluation of Ecological Factors

• Sanitary status of eating establishments
• Water supply and milk supply systems; breakdown in supply
• Movements of human population
• Atmospheric changes (temperature, humidity, air pollution)
• Population dynamics of insects and animal reservoirs

Step 9: Further Investigation of the Population at Risk

• Medical examination and screening tests
• Examination of suspected food, faeces, or blood samples
• Biochemical studies
• Assessment of immunity status
• Serological study may reveal clinically inapparent (subclinical) cases and throw light on pathogenesis
• Healthy individuals from the same area are studied in a case-control fashion to classify all members as: (a) exposed to potential vehicles, and (b) whether ill or not

Step 10: Writing the Report

Summary: 10 Steps at a Glance

Cold Chain System - 5 Mark Answer

Definition

The right vaccine - in the right quantity - at the right place - at the right time - in the right condition (no temperature breaks) - and at the right cost.

Why is it Necessary?

Temperature Sensitivities

Levels of the Cold Chain

Cold Chain Equipment

Storage Equipment

• Pre-fabricated polyurethane foam insulated cold room
• Temperature: -15°C to -25°C
• Has standby generator (auto-starts on power cut)
• Used at national/state level for bulk OPV storage and ice pack preparation

• Similar construction to WIF
• Temperature: +2°C to +8°C
• Used for storage of all UIP vaccines at national/state level

• Top-opening lid (prevents cold air loss)
• Temperature: -15°C to -25°C
• Stores OPV at district level; also freezes ice packs at sub-district level

• Most important link in the cold chain
• Temperature: +2°C to +8°C
• Top-opening design retains cold air better than front-opening fridges
• Has a lining of frozen water containers around walls - maintains safe temperature for minimum 8 hours without electricity
• Used at district and sub-district (PHC) level

Transportation Equipment

• Refrigerated/insulated vaccine vans - for district to sub-district transport
• Cold boxes - passive insulated containers; carry vaccines for 3-5 days with ice packs
• Vaccine carriers - smaller portable containers for field/outreach sessions; maintain +2°C to +8°C for 6-8 hours

Vaccine Vial Monitor (VVM)

Key Points for Cold Chain Maintenance

1. Temperatures must be checked and recorded twice daily (morning and end of session)
2. Freeze-sensitive vaccines (DPT, TT, Hep B) must be stored in the upper basket of the ILR - never on the floor
3. Heat-sensitive vaccines (OPV, BCG, Measles) are kept at the bottom
4. Vaccines should never be kept directly on the floor of the refrigerator
5. One designated person at each health facility must have overall responsibility for the cold chain