METHODOLOGY OF RESERCH

4-5
Rohring et al, 2009
 OBSERVATIONAL vs INTERVENTIONAL
• 1. Non-intervention (Observational) studies in
which the researcher just observes and analyses
researchable objects or situations but does not
intervene.

• 2. Intervention studies in which the researcher

manipulates objects or situations and measures the
outcome of his manipulations (e.g., by implementing
intensive health education and measuring the
improvement in immunisation rates.)
 EXPERIMENT 1
• A researcher assembles
two groups of study
participants with Lyme
Disease. She
administers the antibiotic
doxycycline to one group
and amoxicillin to the
other. The researcher
then measures which
has more of a beneficial
effect.
 EXPERIMENT 2
• A researcher identifies two
groups of elderly immobilized
patients in a nursing home.
One group of patients is
repositioned every two hours.
The other group is
repositioned every 1.5 hours.
The researcher measures
whether the incidence of bed
sores is lower in the group
repositioned every 1.5 hours
than the group repositioned
every 2 hours .
 EXPERIMENT 3
• A researcher develops a
counseling program
designed to increase
medication compliance in
AIDS patients. The
researcher delivers the
program to one group of
patients but not another,
then studies whether the
group that underwent the
counseling program adhered
to their medication better
than the group that did not .
What do all three experiments have in
common?

.
 .

• In each case the researcher actively interfered

with one group of study subjects and then
compared the outcome with a similar group of
subject that did not receive the same
intervention.
• Experiments in which researchers interfere
with their study subjects are known as clinical
investigations.
• All examples above pertain to humans, but
many clinical investigations are done using
animal subjects, particularly for new or risky
interventions.
 EXPERIMENT 1
• A researcher identifies a
group of patients who
were incorrectly
diagnosed with Lyme
Disease, then records
whether the patients
experienced adverse
effects from the
antibiotics they were
prescribed for treatment
of Lyme
 EXPERIMENT 2
• A researcher identifies a
group of elderly immobilized
patients in a nursing home.
The researcher follows the
patients for 6 months and
records the administration of
any topical (skin) agent. At
the end of the study period,
the researcher conducts an
analysis to determine
whether certain topical
regimens related to reduced
incidence of bed sores.
 EXPERIMENT 3
• A researcher identifies
a group of individuals
with AIDS who have
low medication
compliance. The
researcher administers
a questionnaire to the
patients to determine
what factors relate to
their poor compliance
What do all three experiments have in
common?

.
 .

• In each case the researcher does not actively

manipulate or intervene with patients; rather,
the researcher merely observes the effect of
one or more factors on an outcome. It is easy
to see why observational studies received
their moniker.
OPERATIONAL DEFINITIONS OF VARIABLES

• Definition: A variable is a characteristic of a

person, object, or phenomenon that can take
on different values.
 VARIABLES
a) weight in kilograms
b) height in centimeters
c) marital status (single, married, divorced and
widowed)
d) occupation (civil servant, farmer, student)
e) disease condition (presence or absence of a disease)
a and b are numerical variables because they are
expressed in numbers (metric data).
c, d and e are categorical variables.
 ETHICAL PRINCIPLES
1. Autonomy- we ought to respect the right to self-
determination
• IN RESEARCH AUTONOMY IS PROTECTED BY
ENSURING THAT ANY CONSENT TO PARTICIPATE IN
THE STUDY IS INFORMED OR REAL (this means it is
not enough to explain something about your project
to a particular subject, it is the understanding and
free choice whether or not to participate that is the
key issue; here must be no coercion of any sort).
 ETHICAL PRINCIPLES
2. Non-Maleficence- we ought not to inflict evil
or harm
• This principle states that we may not inflict
harm on or expose people to unnecessary risk
as a result of our research project (his is
particularly important if our subjects may not
be competent in some way, such as, the ability
to give informed consent).
 ETHICAL PRINCIPLES
3. Beneficence – we ought to further others’
legitimate interests
• This is the principle that obliges us to take
positive steps to help others pursue their
interests. These interests clearly have to be
legitimate.
 ETHICAL PRINCIPLES
4. Justice-we ought to ensure fair entitlement
to resources
• This principle is concerned with people
receiving their due. This means people should
be treated equally in every way since not all
people are equally competent or equally
healthy.
 ETHICAL ROULES
1. Veracity- All subjects in any research project should always be told the
truth. There is no justification for lying, but this is not the same non-
disclosure of information should it, in particular, invalidate the research.
2. Privacy- When subjects enroll in a research study, they grant access to
themselves, but this is not unlimited access. Access is a broad term and
generally includes viewing, touch or having information about them.
3. Confidentiality- Although someone may grant limited access to him or
herself, they may not relinquish control over any information obtained.
Certainly, no information obtained with the patient’s or subject’s
permission from their medical records should be disclosed to any third
person without that individual’s consent. This applies to conversations too.
4. Fidelity- Fidelity means keeping our promises and avoiding negligence
with information. If we agree for example, to send a summary of our
research findings to participants in a study we should do so.
STUDY DESIGNS COULD BE EXPLORATORY,
DESCRIPTIVE OR ANALYTICAL
1. Exploratory studies is a small-scale study of relatively
short duration, which is carried out when little is known
about a situation or a problem. It may include
description as well as comparison.
• When doing exploratory studies we describe the needs
of various categories of patients and the possibilities for
action. We may want to go further and try to explain the
differences we observe (e.g., in the needs of male and
female AIDS patients) or to identify causes of problems.
Then we will need to compare groups.
STUDY DESIGNS COULD BE EXPLORATORY,
DESCRIPTIVE OR ANALYTICAL
2. Descriptive studies: defined as studies that describe the
patterns of disease occurrence and other health-related
conditions by person place and time.

• Personal variables include: basic demographic factors, such

as age, sex marital status or occupation, as well as the
consumption of various types of food or medication use.
• Characteristics of place refer to the geographic distribution
of disease, including variation among countries or within
countries, such as between urban and rural areas.
STUDY DESIGNS COULD BE EXPLORATORY,
DESCRIPTIVE OR ANALYTICAL
TYPES OF DESCRIPTIVE STUDIES
• a) Case reports and case series
• Case report: a careful, detailed report by one or more clinicians of
the profile of a single patient.
• The individual case report can be expanded to a case series, which
describes characteristics of a number of patients with a given
disease.

Important link between clinical medicine and epidemiology

One of the first steps in outbreak investigation
Often useful for hypothesis generating and examining new diseases,
but conclusions about etiology cannot be made.
 Study designs could be exploratory,
descriptive or analytical
TYPES OF DESCRIPTIVE STUDIES
• b) Cross-sectional studies
• A cross-sectional (prevalence) study provides information
concerning the situation at a given time. In this type of study,
the status of an individual with respect to the presence or
absence of both exposure and disease is assessed at the same
point in time.
-Usually involve collection of new data.
-In general, measure prevalence rather than incidence.
-Not good for studying rare diseases or diseases with
short duration; also not ideal for studying rare exposures.
 Study designs could be exploratory,
descriptive or analytical
b) Cross-sectional studies
• For factors that remain unaltered over time, such as sex, blood
group, etc., the cross sectional survey can provide evidence of a
valid statistical association.
• If data are collected both on exposures and outcomes of
interest, and if the data are analysed so as to demonstrate
differences either between exposed and non-exposed groups,
with respect to the outcome, then this is an analytical cross-
sectional study.
• If the information collected is purely of a descriptive nature, not
involving the comparison of groups formed on the basis of
exposure or outcome status, then this is a descriptive cross-
sectional study.
 Study designs could be exploratory,
descriptive or analytical
3. Analytic studies
• Analytic studies may be defined as studies used
to test hypotheses concerning the relationship
between a suspected risk factor and an outcome
and to measure the magnitude of the
association and its statistical significance.
• Analytic study designs can be divided into two
broad design strategies: Observational and
intervention.
 OBSERVATIONAL
• No human intervention involved in assigning
study groups; simply observe the relationship
between exposure and disease.
• Subject to many potential biases, but by careful
design and analysis, many of these biases can
be minimized.
• Examples of observational studies: comparative
cross-sectional, cohort and case control
studies.
 OBSERVATIONAL- cohort studies

Study groups identified by exposure status

prior to ascertainment of their disease status
and both exposed and unexposed groups
followed in identical manner until they
develop the disease under study, they die, the
study ends, or they are lost to follow-up.
 OBSERVATIONAL- cohort studies

Strengths:
Is of particular value when the exposure is rare
Can examine multiple effects of a single
exposure
Allows direct measurement of incidence of
disease in the exposed and non-exposed
group.
 OBSERVATIONAL- cohort studies

Limitations:
Is inefficient for the evaluation of rare diseases
Expensive and time consuming
Validity of the results can be seriously affected
by losses to follow-up.
 OBSERVATIONAL- case control

Group of subjects with the disease (cases) and

group of subjects without the disease
(controls) are identified. Information, about
previous exposures are obtained for cases and
controls, and frequency of exposure compared
for the two groups.
 OBSERVATIONAL- case control

Strengths:
Is relatively quick and inexpensive
Is optimal for the evaluation of rare diseases.
Can examine multiple etiologic factors for a
single disease.
 OBSERVATIONAL- case control
Limitations:
Is inefficient for the evaluation of rare exposures
Cannot directly compute incidence rates of
disease in exposed and non- exposed
individuals.
Is particularly prone to bias compared with
other analytic designs, in particular, selection
and recall bias.
OBSERVATIONAL- cross-section
 INTERVENTIONAL

• The researcher manipulates a situation and

measures the effects of this manipulation.
• Usually (but not always) two groups are
compared, one group in which the
intervention takes place and another group
that remains ‘untouched’.
 BASIC RESEARCH
• Basic medical research (otherwise known as
experimental research) includes animal
experiments, cell studies, biochemical, genetic
and physiological investigations, and studies
on the properties of drugs and materials.
Incidence from longitudinal studies
• Is a measure of the frequency with which new disease events occur, and
the rate at which people free from the disease develop the disease during
a specified period of observation. A period of one year is commonly used.
• The important aspects of this measure are:
• - the need to define the population of interest; this is often called the
inception cohort;
• - all the persons in the inception cohort should be free of the disease;
• - a period of observation should be specified;
• - all persons should be followed for the specified period of observation;
• - if incomplete follow-up is encountered (some followed up for less than
the specified period), the estimates of the incidence rates should be
appropriately adjusted (i.e. incidence density rather than cumulative
density should be used).
 prevalence
• Prevalence is a measure of the status quo of a disease in a
population at a fixed point of time, or during a specified
period. It is the proportion of people who have the
disease at the specified point or period.
• Prevalence rates are typically obtained from cross-
sectional studies such as national health surveys.
Occasionally, they are based on disease registries
(national or population-specific). Prevalence depends on
previous incidence (I) and the duration of the disease (D).
When both the incidence and duration are relatively
stable, P = I x D.
CLINICAL STUDY CLASSIFICATION
Rohring et al, 2009
CLINICAL TRIALS
 WHAT ARE CLINICAL TRIALS?
• Clinical Trials are medical or health-related
research studies done in human beings (or in
animals if the study is a veterinary study).
• In Clinical Trials, researchers take the results
from basic scientific research and translate
them into ways to prevent, treat, or diagnose
disease.
• Without them, we would could not ensure safe,
effective treatments for diseases.
 THE SCIENTIFIC METHOD
• Clinical Trials are “real
world” applications of the
Scientific Method.
• Each time a drug, medical
device or procedure, is
tested, a question is asked,
a hypothesis is made, an
experiment is conducted,
results are analyzed, and a
conclusion is reached.
 TYPES OF CLINICAL TRIALS
• Treatment Trials - test new treatments, new combination
of drugs or new approaches to surgery or radiation.
• Prevention Trials - look for better ways to prevent diseases
• Diagnostic Trials - determine better tests or procedures
for diagnosing a particular disease or condition.
• Screening Trials - test the best way to detect or treat
diseases.
• Quality of Life Trials - explore and measure ways to
improve the comfort and quality of life of people with a
chronic illness.
CLINICAL TRIALS ARE DONE IN PHASES:

Phase I
• Researchers test an experimental drug or
treatment in a small group of people
(approximately 20-80) for the first time. The
purpose is to evaluate its safety and identify
side effects.
CLINICAL TRIALS ARE DONE IN PHASES:

Phase II
• The experimental drug or treatment is
administered to a larger group of
people/animals (approximately100-300) to
determine its effectiveness and to further
evaluate its safety.
CLINICAL TRIALS ARE DONE IN PHASES:

Phase III
• The experimental drug or treatment is
administered to a large group of
people/animals (300-3,000 or more) to
confirm its effectiveness, monitor side effects,
and compare it with standard or equivalent
treatments.
CLINICAL TRIALS ARE DONE IN PHASES:

Phase IV
• After a drug is licensed (approved by the FDA or
EMA) or treatment is launched, researchers
track its safety, seeking more information about
a drug or treatment’s risks, benefits, and
optimal use. These long-term studies involve
large groups of participants and are designed to
reveal if any unexpected side effects occur in a
small percentage of individuals.
 APPROVAL MUST BE GAINED
• Once a drug has proven satisfactory after Phase III trials,
the trial results are usually combined into a large document
containing a comprehensive description of the methods
and results of human and animal studies, manufacturing
procedures, formulation details, and shelf life.
• This collection of information makes up the "regulatory
submission" that is provided for review to the appropriate
regulatory authorities like the U.S. Food And Drug
Administration (FDA) or European Medicines Agency (EMA)
so they can then grant the sponsor approval to market the
drug, device or treatment.
 RESEARCH CONCEPTS
• A placebo is a product that looks like the new drug, but it does not
have the active ingredient in it. People do not know that they are
getting the placebo
• A Blind Trial is a trial in which the patients do not know if they are
receiving the treatment or a placebo.
• A Double Blind Trial is a trial in which the patients and the
researchers do not know who is receiving the treatment.
• Screening is the period when the patients are investigated in order to
be fit for randomization.
• Randomization is the process by which patients are assigned a group
for the Clinical Trial. Groups are assigned randomly, not purposefully.
 BIAS
• Bias is a systematic distortion of a result due to a factor not
allowed for in the design of the study.
For example, bias would occur if, when testing two different
treatments, the two groups were given tablets that looked
different; or if one group was given a tablet and the control
group was not given a tablet. The two groups of patients are
managed differently and it is possible the these differences
might influence the trial results.
Ex: Hawthorne effect: the presence of the researcher affects
the behavior of the subjects
.
.
CLINICAL TRIAL: STUDY DESIGN
 Uncontrolled
 Controlled
 Before/after (cross-over)
 Historical

 Concurrent, not randomized

 Randomized
 NON-RANDOMIZED TRIALS
MAY BE APPROPRIATE

• Early studies of new and untried therapies

• Uncontrolled early phase studies where the

standard is relatively ineffective

• Investigations which cannot be done within the

current climate of controversy

• Truly dramatic response

 ADVANTAGES OF RANDOMIZED
CONTROL CLINICAL TRIAL

1. Randomization "tends" to produce comparable

groups

2. Assure causal relationship

3. Randomization produces valid statistical tests

 DISADVANTAGES OF
RANDOMIZED CONTROL CLINICAL
TRIAL
1. Generalizable Results?
– Participants studied may not represent general
study population.

2. Recruitment
– Hard

3. Acceptability of Randomization Process

– Some physicians will refuse
– Some participants will refuse

4. Administrative Complexity
 PROTOCOL OF A CLINICAL TRIAL
1.Definition
2.Importance
3.Format
(a) Title page
(b) background and hypothesis
(c) Study design
(d) Materials and methodology
(e) Data collection and handling
(f) Statistical analysis
(g) References
(h) Summary
 CLINICAL PROTOCOL (1)
• Background/Justification
--Where we are in the field
--What the study will add that is important
• Objectives
--Primary hypothesis
--Secondary hypotheses
--Other
 STUDY POPULATION
Subset of the general population determined by the
eligibility criteria

General population
Eligibility criteria

Study population
Enrollment

Study sample
Observed
 CLINICAL PROTOCOL (2)
• Study Design and Methods
– Type of study, comparison
– Inclusion and exclusion criteria
– Description of intervention (what, how)
– Concomitant therapy
– Examination procedures (baseline, follow-up, outcome
assessment)
– Intervention assignment procedure
– Data collection sheet
– Informed consent
 INFORMED CONSENT
• Voluntary Informed Consent is essential for research
involving human subjects
• Informed Consent should include:
– Description of the nature of the research
– Statement that the research is voluntary and participants
can withdraw at any time
– Identification of Risks and Benefits
– Description of how confidentiality will be protected
– Description of compensation
– Description of what info researchers will share with
participants
– Identification of who is responsible for research with
contact information
 CONFIDENTIALITY
• All information collected in a research project
should remain confidential
– Participants should be assigned a HIPAA compliant
code
– Data should be locked away in a secure setting
– Electronic Databases should also be protected
 ELIGIBILITY CRITERIA
(INCLUSION & EXCLUSION)

• State in advance
• Consider
– Potential for effect of intervention
– Ability to detect that effect
– Safety
– Ability for informed consent

77
 METHOD OUTLINES
• The independent (predictor) and dependent (outcome)
variables in the study should be clearly identified, defined,
and Measured?
• How to choose subjects?
– Random or not
– Are they going to be representative of the population?
– Random selection is not random assignment
• Types of Blinding (Masking) Single, Double, Triple.
• Control group? How is it chosen?
• How are patients followed up? Who are the dropouts?
• How is the data quality insured? Reliability?
• Consider independent review of data? Compliance?
 COMPARING TREATMENTS
a) Fundamental principle
• Groups must be alike in all important aspects and only differ
in the intervention each group receives
• In practical terms, “comparable treatment groups” means
“alike on the average”
b) Randomization
• Each participant has the same chance of receiving any of the
interventions under study
• Allocation is carried out using a chance mechanism so that
neither the participant nor the investigator will know in
advance which will be assigned
c) Blinding
• Avoidance of conscious or subconscious influence
• Fair evaluation of outcomes
 METHODS OUTLINES (2)
• Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria
 REGULAR FOLLOW-UP
• Routine Procedures (report forms)
– Interviews
– Examinations
– Laboratory Tests
• Adverse Event Detection/Reporting
• Quality Assurance