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Presentation at a workshop on Research Methodology in Health Sciences held at the Northern Area Armed Forces Hospital on 29 December 2020 at 7.10 pm. By Professor Omar Hasan Kasule MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics, King Fahad Medical City
DEFINITION OF EXPERIMENTAL STUDIES:
} Experimental studies involve deliberate human
action or intervention whose outcome is then observed. Their objective is to
establish a definitive causal relation.
} Examples of experimental studies involving
humans: clinical therapeutic trials, community intervention studies to assess
vaccines, community interventions to assess preventive measures, etc.
} Main characteristics of an experimental
design are a random selection, random assignment, manipulation of independent
variables by the experimenter, and control of all other variables by the
experimenter without manipulating the outcome (dependent variable).
} Experimental studies can be natural
experiments or true experiments.
NATURAL EXPERIMENTS:
} Natural experiments are not
designed by humans. Humans only observe and benefit from their results.
} Examples of natural
experiments.
§ Snow's study of cholera in
London: he found cholera to be related to the source of the water supply.
§ In the 1950s air pollution
episodes led to mortality in London and Los Angeles.
§ Increased death and leukemia
in atomic bomb survivors in Hiroshima and Nagasaki.
TRUE EXPERIMENTS:
} True experiments are more
involved and more expensive than observational studies or natural experiments
but are still cheaper and easier than laboratory-based research.
} Classical examples of true
experiments before World War 2 were not as complicated as today’s experiments
but were run on similar basic principles.
TRUE EXPERIMENTS con’t. - 1:
} In 1754 Dr. James Lind published the results of his trial of citrus fruit juice to prevent scurvy among sailors. He
studied 12 sailors who were given a standard diet. They were allocated to 6
treatment groups that received various treatments for a period of 14 days.
} 1796 Edward Jenner's cowpox
vaccination to prevent childhood disease. Inserted pus from a cowpox pustule in
the arm of 8 year James Phipps who subsequently became immune to smallpox
(copied from Ottomans by Lady Montagu wife of the British Ambassador in
Istanbul).
TRUE EXPERIMENTS con’t. - 2:
} In 1886 Cuban epidemiologist Juan Carlos
Finlay published his experiments on the transmission of yellow fever to humans
by the mosquito. He started by recruiting 20 volunteers, 5 were experimental
and 15 were controls. He used mosquitoes that had bitten yellow fever to bite
his subjects who subsequently developed yellow fever. He continued the
experiment with more volunteers.
} In 1900, US Army Surgeon Dr. Walter Reed confirmed
Finlay’s findings.
TRUE EXPERIMENTS con’t. - 3:
} 1915 Joseph Goldberger using dietary
intervention discovered the dietary cause of pellagra. In 1937 niacin
deficiency was identified as the cause of pellagra.
} 1905 William Fletcher in Kuala Lumpur
carried out an experiment that proved that beri beri was more in patients
fed white rice than in those fed brown rice. His work was based on earlier
research in 1889 by Christian Eijkman who had found beri beri symptoms in
chickens fed white rice but the symptoms disappeared when they were fed brown
rice.
STRENGTHS OF EXPERIMENTAL STUDIES:
} The main strength of experimental studies is a good control for confounding.
} Randomization in experimental studies is the
basis for unequivocal evidence of causality.
} The experimental design enables the
investigator to control extraneous variables.
} The experimental design enables the
investigator to vary the levels of independent variables in order to make a
more thorough and detailed study.
WEAKNESSES OF EXPERIMENTAL STUDIES:
} The main weakness of experimental studies is
that well-controlled experiments on humans are difficult to carry out and have
ethical problems.
} It is difficult to put humans under full
experimental conditions where they can be observed for 24 hours.
} Ethical controversies and violations of human
rights always arise in such studies.
POPULATIONS:
} The target population is the big population to which the results of the experiment will be
applied.
} Study population: A
study population suitable for the problem being studied must be selected. It
may represent the general population or may be restricted to certain groups.
Economic and logistic considerations affect the selection of the study
population.
POPULATIONS con’t.:
} Sample are the actual people
selected from the study population for the experiment. A representative sample
is not necessary for the validity of an experimental study.
} Study groups: The researcher determines
the experimental or intervention group (who will get the exposure studied) and
the comparison group. The control group could get the exposure studied unknown
to the investigator. Even after randomization, the experimental and comparison
groups may not be comparable.
FIGURE:
RANDOMIZATION: Definition and Objectives
} Randomization is the basic sampling scheme
for experimental studies and clinical trials. It is the main sampling design
used in experimental studies.
} Randomization involves the allocation of subjects
by independent random choice to 2 or more experimental groups.
} The objective of randomization is to prevent
investigator bias in the selection and allocation of subjects to the treatment and
reference groups, ensure comparability of results from the two groups, and
increase confidence in the results of the study.
RANDOMIZATION: Definition and Objectives con’t.:
} Randomization balances the distribution of confounding
as well as prognostic factors and assures the accuracy of statistical tests.
} Randomization is not successful with small
samples and does not always ensure correct conclusions.
RANDOMIZATION: Methods
} Alternate cases.
} Sealed serially numbered envelopes.
} Random numbers.
RANDOMIZATION: Enhancements
} Randomization has the objective of balancing
the distribution of confounding factors, known and unknown, across groups. This
purpose is not always achieved to 100% perfection.
} To obtain more balancing of confounding
randomized block design is used in which the randomization process is carried
out separately for each 'block'. The block could be a gender or age group.
} Stratified randomization is akin to the block
design of experimental studies.
RANDOMIZATION: Parallel and Crossover
} Once the 2 groups are identified, the study
may be carried out in parallel or it may use the cross-over design.
} In the parallel design the experimental and
comparison groups are followed until the end.
} In the crossover there is an exchange. The
experimental group becomes the comparison group during the trial and vice
versa. Thus, subjects in both groups will take turns receiving the material
being tested.
RANDOMIZATION: Alternatives
} Where randomization and selection of a good
control group are not possible, quasi-experimental studies may be carried out.
} Non-randomized trials can be carried out
where randomization proves difficult, but they are far less valid than randomized ones. They obtain comparison groups by using either historical
controls or by carrying out pre-and post-test assessments.
ETHICAL ISSUES IN CLINICAL TRIALS:
} Individual rights/welfare vs community
benefit: why should a patient take a risk to discover a new treatment that will
benefit future patients?
} Randomization: control/placebo group does not
benefit, or the experimental group is exposed to danger.
} Informed consent and coercion in the
vulnerable.
} Conflict of interest.
} Confidentiality.
} Publication malpractices: no publication,
publication bias.
FURTHER READING:
} The Oxford Textbook of Clinical Research
Ethics.