desain penelitian overview - dr. kuntjoro harimukti, sppd(k)

8/13/2019 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

[email protected]


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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...

desain penelitian overview - dr. kuntjoro harimukti, sppd(k)

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