EXPERIMENTAL EPIDEMIOLOGY

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HIERARCHY OF

EVIDENCE

INTRODUCTION An experiment is: the final or definitive step in the research process, a mechanism for confirming or rejecting the validity of ideas,

assumptions and hypothesis.

The Randomized Controlled Trial (RCT) is the most scientifically rigorous method of hypothesis testing available

GOLD STANDARD TRIAL evaluating the effectiveness of interventions

AIMS To provide: "scientific proof" of etiological factors. A method of measuring the effectiveness and efficiency of health services.

EXPERIMENTAL

EPIDEMIOLOGY

ANIMAL STUDIES

HUMAN EXPERIMEN

TS

HUMAN EXPERIMENTS Human experiments will always be needed to investigate disease aetiology and to evaluate the preventive and therapeutic measures.

History: James Lind (1747): Study on scurvy

CLASSIFICATIONRandomized controlled trials• those involving a process of random

allocationNon – randomized trials • those departing from strict randomization

for practical purposes, but in such a manner that non-randomization does not seriously affect the theoretical basis of conclusions.

RANDOMIZED CONTROLLED TRIALS

(RCT’s)

Essential elements of a clinical trial1. Prospective

Subjects followed forward2. Intervention

Prophylactic, diagnostic or therapeutic3. Control

Compared to intervention group4. Randomized

Equality of baseline characteristics5. Blinded

Systematic bias

Structure of a clinical trial

Steps in clinical trial1. Drawing up a protocol2. Selecting reference and experimental

populations3. Randomization4. Manipulation or intervention5. Follow-up6. Assessment of outcome

THE PROTOCOLThe aims and objectivesQuestions to be answeredCriteria for the selection of study and control groupsSize of the sample, Procedures for allocation of subjects Treatments to be appliedStandardization of working proceduresSchedules Responsibilities of the parties

Clinical trial question Type of research question determines the trial design For a research question addressing an intervention:

P • POPULATIONI • INTERVENTIONC • COMPARISONO • OUTCOMET • TIME

For adult patients, will the use of a powered toothbrush, compared to a manual toothbrush, result in reduction in plaque

and/or gingivitis?

P I

C O

TRY THIS

SELECTING REFERENCE AND EXPERIMENTAL POPULATIONSREFERENCE OR TARGET POPULATION:It is the population to which the findings of the trial, if found successful, are expected to be applicable.

EXPERIMENTAL OR STUDY POPULATIONThe study population is derived from the reference population, on which the study is conducted..

RANDOMIZATION

Of a clinical trial

PREDICTABILITY The critical element of randomization is the unpredictability of the next assignment

RANDOMIZATION Randomization is a statistical procedure by which the participants are allocated into groups usually called “study” and “control” groups.

Elimination of “selection bias”

Three common randomization schemesSimple RandomizationStratified RandomizationCluster Randomization

Randomization Objective of randomization Everyone in the study has an equal probability of

being offered each intervention All prognostic variables, known and unknown,

have an equal distribution in the treatment groups in the long run

Methods of randomization Simple randomization

Stratified randomization

Clustered randomization

MANIPULATION The next step is to intervene or manipulate the study (experimental) group by the deliberate application or withdrawal or reduction of the suspected causal factor or drug or treatment.

FOLLOW-UPThis implies examination of the experimental and control groups:at defined intervals of time, in a standard manner, with equal

intensity, under the same given circumstances, in the same time frame till final

assessment of outcome.

ASSESSMENT The final step is assessment of the outcome of the trial in terms of-

Positive results- reduced incidence or severity of the disease, cost to the health service or other appropriate outcome.

Negative results- severity and frequency of side-effects and complications.

The incidence of positive/negative results is rigorously compared in both the groups.

BIAS IN CLINICAL TRIALS Bias may arise from errors of assessment of the outcome due to human element-

SUBJECT VARIATION

OBSERVER BIAS

EVALUATION BIAS

BLINDING/MASKINGIt is the procedure of keeping the knowledge of intervention assignment away from those directly involved in the trial.

Ensures that the outcome is assessed objectively.

Can be done in three ways-Single Blind TrialDouble Blind TrialTriple Blind Trial

https://www.google.co.in/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiA2obGzo_TAhUKtY8KHTZ9CG4QjRwIBw&url=https://www.youtube.com/watch?v=n0q_rLSBZFY&bvm=bv.151426398,bs.1,d.cGc&psig=AFQjCNEuHogd_Y413jtBQf1hoabUrvHNUw&ust=1491560223918404

BASIC DESIGNS OF CLINICAL TRIALSBasic two-arm parallel design

Cross over design

Factorial design

PHASES OF CLINICAL TRIAL

Types of clinical trialsEffectiveness: Examine the outcomes of interventions under circumstances that more closely approximate the real world

Efficacy: Investigates the benefits of an intervention under ideal and highly controlled conditions

Other types of clinical trials . . .

Preventive trialsRisk factor trialsCessation experimentsEvaluation of health servicesField trialsCommunity trials

NON-RANDOMIZED TRIALS• It is undertaken when:

• Not feasible to conduct RCT

• Secondly, some preventive measures can be applied only to groups or on a community-wide basis.

• Thirdly when natural history of disease is long

Examples of non-randomized trialsUncontrolled trials

Natural experiments

Before and after studies

ADVANTAGES •Safety: relatively few individuals exposed to unpredicted risks in untried interventions.

•Vigour : capable of critical tests of limits of applicability.

•Precision: theorized causal factor can be defined and limited exposure of test factor under control of researcher.

•Efficiency: relatively few observations needed to refute some hypothesis.

•Assumptions: random allotment of treatments is assured by the design.

DISADVANTAGESImpracticality: inborn attributes cannot be manipulated.Predicted risk of intervention is great. Long term observation is difficult. Large number of subjects needs to detect small differences.Reductionism: focus on one independent variable excludes others from attention.Representativeness: difficult to recruit a truly random sample from ‘universe’.Expense: relatively great in staff and logisticsPublic acceptance: undue suspicion of outcomes.

SummaryHierarchy of evidenceAims of experimental epidemiologyClassification of experimental studiesRandomized controlled trials1. Structure2. Steps3. Blinding4. Basic designs5. PhasesNon-randomized trialsAdvantagesDisadvantages

References and suggested readingPARK K. PARK’S TEXTBOOK OF PREVENTIVE AND SOCIAL MEDICINE. 21st ed. Jabalpur: Banarsidas Bhanot; 2011.

Soben Peter. Essentials of Preventive and Community Dentistry. 4th ed.

Kendall JM. Designing a research project: randomised controlled trials and their principles. Emerg Med J. 2003 Mar 1;20(2):164–8.