Desain Penelitian Overview - Dr. Kuntjoro Harimukti, SpPD(K)
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Transcript of Desain Penelitian Overview - Dr. Kuntjoro Harimukti, SpPD(K)
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Study Designs
in Clinical Research:An Overview
Kuntjoro Harimurti
Department of Internal MedicineCenter for Clinical Epidemiology and EBM (CE-EBM)
Cipto Mangunkusumo Hospital / Faculty of Medicine UI, Jakarta
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...a poor design cannot be salvaged by a
good statistics
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Research Design
A specific plan or protocol for conducting the
study, which allows the investigator to
translate the conceptual hypothesis into anoperational one
All procedures for selecting and recruiting
individuals in the study sample
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Consideration when choosing a
study design
No one approach is always better than the
others
Each research question requires a judgmentabout which design is the most efficient way
to get a satisfactory answer
Its choose depends on the study objectives,
but may also rely on practical issues such ascosts or data availability
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Clinical Study Types
Observational Studies
Case report
Case series
Cross-sectional
Case-control
Cohort
Experimental Studies Uncontrolled
Controlled
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Observational Studies
A study in which the investigator
monitors, but does not influence, theexposure status of individual subjects and
their subsequent disease status
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Case-report and case series
Not considered to be true investigation
Only describe clinical / laboratory
characteristics
No hypothesis, no statistical analysis, no
sample size estimation
Involve new disease, rare disease, or rare
manifestations of common diseases
Sometimes useful to identify research
problem and generating hypothesis
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Cross-sectional study
A study in which determinant (risk factors)
and outcome (disease) are collected at the
same point in time for each participant
Characteristics of cross-sectional study:
Observational = non-experimental
No time-axis
Individual observed only once
Could be descriptive or analytic
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Use of cross-sectional studies
Prevalence studies (descriptive): survey, census
Etiologic studies Determinant characteristics that do not change (sex,
gene expression)
Diagnostic studies Estimate probability of disease presence on basis of
diagnostic determinants
Reference range studies
Repeated cross-sectional studies Measure change / evaluate intervention
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Measures and analyses
in cross sectional studies
Categorical variables
Prevalence, percentage
Prevalence ratio
Odds ratio
Numerical variables
Mean Means difference
Correlation coefficient
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Case-control study
I would trust only six people in the world to doa proper case-control study (David L. Sackett)
A study in which outcomes (disease/cases andno-disease/controls) identified first and riskfactors accounted in and compared betweencases and controls
Characteristics of case-control study: Observational
Retrospective Analytic
Essence of case-control study: sampling!
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Analysis in case-control studies
Objective: to measure association, estimating
relative risk/risk ratio (RR)
Risk could not directly calculated from a case-
control dataalternative measure: odds Odds: probability of event / probability of no-event
(p/1-p)
Odds ratio (OR): ratio of two odds (with CI and p-
value) Interprete cautiously as RR (risk ratio or relative
risk)
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Cohort study
Cohort: the tenth division of the Roman army.
Cohort of war fighters
In research: a cohort is a group of subjects
from which data are collected
Cohort studies: disease-free subjects
selected first according to the risk factor and
further followed for the disease Prospective and restrospective cohort
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Analysis in cohort studies
Measuring incidence: Cumulative incidence (risk)
Incidence density: person-time
Measuring (strength of) association: Risk ratio/relative risk (RR) Sometimes expressed as OR
With p-value and CI
Special analysis in cohort studiessurvivalanalysis: Time to event as outcome
Calculating prob. of survival in a specific period
Measure of association: hazard ratio (HR)
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Observational Designs
Today
Participants,
Patients,
Subjects
Cases
Controls
E
(+)
E(-)
E(+)
E(-)
Retrospective
Cohort
Case-control
Cases Controls
E(+) E(-)E(+) E(-)
Exposure
NoExpo.
Case
Control
Case
Control
Prospective Cohort
Cross-sectional
Time
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Comparisons of
observational study designs
Cross-
sectional
Case-
control
Retrospective
Cohort
Prospective
Cohort
Time - - - ++
Cost + + + +++
Loss to follow
up
- - + ++
Estimating risk
/ RR
+ ++ +++ +++
Bias + +++ ++ +
Cause-effect
relationship
+ ++ +++ +++
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Experimental Study
A study in which the investigator
influences the exposure status of
individual subjects and then monitors the
subjects outcome
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Types of experimental studies (trials)
Blinded Not blinded
Randomised Not randomised
Controlled Not controlled
Trial
A randomized double-blind controlled clinical trial (RCT)
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Clinical Trial
A randomized double-blind controlled clinical
trial (RCT)
Gold standard of research design which
provide the most convincing evidence ofrelationship between exposure (intervention)
and outcome
Use human subject Always prospective
Comparing two or more intervention
strategies
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Clinical Trial
Key elements of RCT:
Randomization
Blinding
Control
Comparabilities in RCT:
Comparability of prognostic factors
Comparability of extraneous factors Comparability of outcome measures
Objective:
To achieve
comparabilities
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Clinical Trial: Parallel Group Design
Participantsscreened for
entry criteria
Control
Treatment
Experimental
Treatment
W
ithout
Ou
tcome
With
Outcome
Without
Outcome
With
Outcome
Time
Screening Baseline Treatment
R
Outcomemeasurement
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Analysis in RCT
Numerical outcome:
Means or medians difference after intervention
(Student -t test or Mann-Whittney test)
Per-protocol analysis
Categorical outcome:
Relative risk (RR), hazard ratio (HR)
Relative and absolute risk reduction (RRR, ARR) Number needed to treat (NNT
Intention-to-treat analysis
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META-ANALYSIS
Special Design in Clinical Research
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Meta-Analysis
Quantitative method of combining the results of
independent research (primary) studies and
synthesizing conclusions to evaluate the
effectiveness of treatments or procedures
Begins with systematic finding, evaluating, and
presenting the results of primary studies
Systematic Review
No collecting data directly from the study subjects
secondary research
Considered as true investigation and has highest
rank in level-of-evidence
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Advantages of Meta-analysis
Quantitatively summarize estimate from
previous studiesresolve controversies
Using protocol to choose the individual
studiesavoid bias Increase power for statistical test and
increase precision for confidence intervals
Conclusions often reflect broad spectrum ofpatient and characteristicsresults are
more generalizable
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Study I 1992Study II 1994Study III 1995
Study IV 1995Study V 1996Study VI 1997Study VII1 1999Study VIII 2000
Combined
0.1 10OR = 1
Favor drug Favor placebo
Meta-analysis of RCTs
with nominal outcome
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Study I 1992Study II 1994Study III 1995
Study IV 1995Study V 1996Study VI 1997Study VII1 1999Study VIII 2000
Combined
-1.0 +1.0Mean difference (X1-X2) = 0
Favor drug Favor placebo
Meta-analysis of RCTs
with numerical outcome
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Clinical Research
Clinical research involves working with human
subjects to answer questions relevant to their
well-being
Clinical (epidemiology) research addresses
questions regarding clinical practice challenges
Patient oriented research is where the rubbermeets the road!
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Challenges in clinical practice
1. Explanation of clinical profile: given the patient
profile, what the patients illness?
2. Explanation of illness: why did this illness
occur in this patient at this time?
3. Prediction of course: given the patients
illness, its etiology, the clinical and non-
clinical profile, etc., what will be the future
course of the illness, depending on (absenseof) treatment
4. Treatment decision
5. Treatment execution
Diagnostic
knowledge
Etiologic
knowledge
Prognostic
knowledge
Prognostic and
decision analysis
Skill
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Diagnostic research
Aim: to predict the probability of presence of
target disease from clinical and non-clinical
profile
Relevance for patient and physician to establishdiagnosis and guide management
Results presentation: sensitivity, specificity,
positive and negative predictive values,
likelihood ratios, scoring system
Example: Wells clinical prediction rule for DVT
and PE
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Wells clinical prediction rule for DVT
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Etiologic research
Aim: to causally explain ocurrence of target
disaese from determinant (risk factor)
Research relevance may indicate means of
prevention and causal intervention Results presentation: odds ratio (OR), relative
risk (RR), hazard ratio (HR)
Example: smoking and lung cancer study bySir Bradford Hills
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Prognostic Research
Aim: to predict of disease from clinical and
non-clinical profiles
Relevance for patient and physician to learn
about future and guide management Results presentation: RR, HR, predictive
values, scoring system
Example: TIMI risk score for STEMI,Framingham Risk Score, CURB-65 score
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Therapy/Interventional research
Aims: To casually explain and to predict the
course of disease as influence by treatment
Relevance for patient and physician to decide
an optimal management and for drugresearch/development/registration
Results presentation: absolute/relative risk
reduction (ARR/RRR), number needed to
treat (NNT)
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The Scandinavian Simvastatin
Survival Study (4S)
Primary Endpoint: Overall Survival
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The Scandinavian Simvastatin
Survival Study (4S)
Summary of Key Endpoint Results
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Choosing design in clinical research should
follow the nature of clinical challenges :
Diagnosticcross-sectional
Etiologic cohort > case-control > cross-
sectional
Prognosticcohort > case-control
TherapyRCT > cohort > case-control
Take home messages
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Thank you...