Interventional Study

Experimental Epidemiology

Dr. Sijal Fadhil Farhood AL-joborae
F.I.C.M.S M.Sc. M.B.Ch.B.

• In the 1920s,experimental epidemiology meant a study of epidemics among colonies of experimental animals such as rats and mites, in modern usage, experimental studies are often equated with RANDOMIZED CONTROLLED TRIAL.

• Experimental or interventional studies are similar in approach to cohort studies except that the conditions in which study is carried out are under the direct control of the investigator.
• Thus the experimental studies involve some action, intervention or manipulation such as deliberate application or withdrawal of the suspected cause or changing one variable in the causative chain in the experimental group while making no change in the control group, observing and comparing the outcome of the experiment in both the groups.

• In contrast with observational studies(case-control and cohort studies) in which the epidemiologist takes no action but only observes the natural course of events or outcome.

Aims of experimental studies

• 1-To provide scientific proof of etiological or risk factors which may permit the modification or control of those diseases.
• 2-To provide a method of measuring the effectiveness and efficiency of health services for the prevention ,control and treatment of disease and improve the health of the community.

• Experimental studies have all the advantages and disadvantages of the usual prospective cohort studies plus three additional problems,(cost,ethics,and feasibility)

Animal studies

• Throughout history animals have played an important role in man’s quest for knowledge about himself and his environment.
• Animal studies have contributed to our knowledge of anatomy,physiology,pathology,microbiology,immunoloygenetics,chemotherapy and so many others.


Important applications of animal experiments
1-Experimental reproduction of human disease in animals to confirm etiological hypothesis and to study the pathogenic phenomena or mechanisms.
2-Testing the efficacy of preventive and therapeutic measures such as vaccines and drugs.
3-Completing the natural history of the disease.

Advantages and limitations of animal studies

• Advantages: The experimental animals can be bred in the laboratories and manipulated easily according to the wishes of the investigator.
• Limitations:
• Not all human disease can be reproduced in animals.
• All the conclusions derived from animal experiments may not be strictly applicable to human beings.

Human experiments

Human experiments will always be needed to investigate disease etiology and to evaluate the preventive and therapeutic measures, These studies are even more essential in the investigation of diseases that can not be introduced in animals.

Although the experimental method is unquestionably the most incisive approach to scientific problem, ethical and logistic considerations often prevent it’s application to the study of disease in human.
Therefore, before doing human experiments, the benefits of the experiments have to be weighed against risks involved.
The volunteers should be made fully aware of all possible consequences of the experiment.

Types of experimental studies

1-Randomized controlled trials (i.e those involving a process of random allocation).
2-Non-randomized or non-experimental trial(i.e. those departing from strict randomization for practical purposes, but in such manner that non-randomization does not seriously affect the theoretical basis of the conclusions)


Randomized controlled trials(RCT)
The basic steps in conducting the RCT include the following:
1-Drawing up a protocol.
2-Selecting reference and experimental populations.
3-Randomization.
4-Manipulation or intervention.
5-Follow-up.
6-Assessment of outcome.

1-Drawing up a protocol: It specifies aims and objectives of the study, question to be answered, criteria for the selection of study and control groups, size of the sample, the procedure for allocation of subjects into study and control groups, treatment to be applied….etc.
2-Selecting reference and experimental populations:
A: Reference or target population: it is the population to which the finding of the trial ,if found successful, are expected to be applicable (e.g. drug, vaccine),a reference population may be as broad as mankind or it may be geographically limited or limited to person in specific age, sex, occupation, thus it may comprise the population of a whole city or a population of school children ,industrial workers ..etc according to the nature of the study.

• B- Experimental or study population:

• It is derived from reference population ,it is the actual population that participates in the experimental study ,it should be randomly chosen from the reference population so that it has the same characteristics as the reference population because if not, we can not generalize the finding of the study to the reference population.
• It is important to choose a stable population whose cooperation is assured (to avoid loss to follow up)
*compliance: is important in intervention studies for the whole period of the study, so non compliance will decrease the statistical power of a trial to detect any true effect of the study treatment.

Criteria of the participants or volunteers

1-They must give informed consent.
2-They should be representative of the population to which they belong (reference population).
3-They should be eligible for the trial.


3-Randomization: (it is a heart of control trial)
is a statistical procedure by which a participants are allocated into study group (in which intervention is given) and control group (in which intervention is not given).
Randomization is an attempt to eliminate bias(selection bias) and and allow comparability

4-Manipulation or intervention: This creates an independent variable(e.g. drug , vaccine, a new procedure) whose effect is then determined by measurement of the final outcome ,which constitutes the dependent variable (e.g incidence of disease, survival time, recovery period).

5-Follow-up: This implies examination of the experimental and control groups at a defined interval in times, in a standard manner, with equal intensity, in the same time frame till the final assessment of outcome.
6-Assessment:
A-Positive results
B-Negative results
The incidence of positive/negative results is compared in both groups and the differences are tested for statistical significance.

• Bias may arise from errors of the assessment of the outcome due to human elements.

• Sources of bias are:
• 1-There may be bias in the part of participants, who may subjectively feel better or report improvement if they knew they were receiving a new form of treatment this is known as subject variation.
• 2-there may be observer bias ,that is the investigator measuring the outcome of the therapeutic trial may be influenced if he knows beforehand the particular procedure or therapy to which the patient has been subjected, this is known as observer bias .
• 3-there may be bias in evaluation, that is the investigator may give a favorable report of the outcome of the trial .
• Randomization can not guard against these sort of bias.

In order to reduce these problems ,a technique known as blinding is adopted which will ensure that the outcome is assessed objectively.
Blinding can be done in three ways:
1-Single blind trial: the trial is so planned that the participants is not aware whether he belongs to the study group or control group.
2-Double blind trial: the trial is so planned that neither the doctor nor the participant is aware of the group allocation and the treatment received.
3-Triple blind trial: The participants, the investigator and the person analyzing the data are all blind.
double blind is most frequently used method when a blind trial is conducted.


Study designs of controlled trial
1-Concurrent parallel study design.
Comparisons are made between 2 groups :
A: Experimental group (which is exposed to specific medication or intervention).
B:Reference group(which is not exposed to specific medication or intervention).
2-Cross-over types of study design: Comparisons are made between 2 groups :
A: Experimental group (which is exposed to specific medication or intervention).
B: Reference group(which is not exposed to specific medication or intervention).
Then the groups are crossed-over (exposed group now becomes non-exposed and vise versa)

Types of randomized controlled trials

1-Clinical trials: it have been concerned with evaluating therapeutic agents, mainly drugs.
Example: trials of folate treatment/supplementation before conception to prevent recurrence of neural tube defects, trial of aspirin on cardiovascular mortality and beta carotene on cancer incidence.
2-Preventive trials: it implies trials of primary preventive measures, these trial are purported to prevent or eliminate disease on an experimental basis, e.g. trials of vaccines.
3-Risk factors trials:
4-Cessation experiments:
5-Trial of etiological agents:
6-Evaluation of health services.


Types of randomized controlled trials
1-therapeutic(or secondary prevention)trial.
determines the ability of the agent or procedure to diminish symptoms, prevent recurrence, or decrease death from the disease.
2-preventive(or primary prevention) trial.
could be done on the whole community, called community trials (prophylactic study)on healthy people like vaccine trial.

Non-RANDOMIZED TRIAL

• It is not always possible for ethical, administrative and other reasons to resort to a randomizes controlled trial in human being, in such situation non-randomized trial is used.
• As there is no randomization the degree of comparability will be lowered the chances of spurious result is high.

Types of Non-RANDOMIZED TRIAL

1-Uncontrolled-trials:control groups is not used for example effectiveness of pap test for cervical cancer.
2-Natural control(natural experiments):natures has separated the population in two groups for example in respect to cigarette smoking ,people have separated themselves into two groups smokers and non smokers.
3-Before and after comparison study(pre-post clinical trial):these study center round comparing the incidence of disease before and after introduction of a preventive measures.

Thank you