in clinical research - med.mahidol.ac.th...rational (e.g. scientific rational) ease of...
TRANSCRIPT
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Introduction & Measurement in Clinical Research
Assistant Professor Sakda A Vallibhakara, MD., PhD., MSIT, MA.IS
Pediatrics, Pediatric Cardiology
Emergency Medicine, Pediatrics Emergency, Family Medicine
Section of Clinical Epidemiology and Biostatistics
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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http://www.ceb-rama.org or http://med.mahidol.ac.th/ceb
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2 modules in 1 Course
1. Clinical Epidemiology (mandatory)
2. Biostatistics for research (mandatory)
3. English for presentation and publication (No class this years 2017)
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How to Access ?
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Agreement Criteria/Rules • Plan I
“Must attend 70 % of Mandatory class” (Eligible for final examination)
• Examination
• Fast Track of consultation services
• Received certify of EBM Certification from faculty of Medicine
• Plan II • Online : E-learning
• Examination
• Plan I- Divided in 2 Part (Passing > 70% in 2 attempts)
• Plan II (E-learning)-Divided in 2 Part (Passing > 80% in 2 attempts)
• Clinical Epidemiology 15 ขอ้
• Biostatistics 15 ขอ้
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Final Examination Residents 2014
Pass, 77, 84%
Fail, 15, 16%
All Exam = 92
Pass Fail
Example of Results
5 % in 2016 Academic Years
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Final Examination Residents 2014
Anesthesiology
Emergency
FamilyMedicine
Obstetricsand
Gynecology
Orthopaedics
Otolaryngology
Pathology Radiology Rehabiltation
Surgery
Exam 14 2 6 8 8 6 4 22 4 18
Eligible 15 2 6 8 8 6 4 22 4 19
All 15 14 6 8 9 6 6 22 5 23
15 14 6 8 9 6 6
22
5
23
15
2
6 8 8
6 4
22
4
19
14
2 6
8 8
6 4
22
4
18
Residents Data
All Eligible ExamExample of Results
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Final Examination Residents 2014
Anesthesiology
Emergency
FamilyMedicine
Obstetricsand
Gynecology
Orthopaedics
Otolaryngology
Pathology Radiology Rehabiltation
Surgery
Fail 5 0 0 0 0 0 1 0 0 9
Pass 9 2 6 8 8 6 3 22 4 9
Exam 14 2 6 8 8 6 4 22 4 18
14
2 6 8 8 6 4
22
4
18
9
2
6 8 8
6 3
22
4
9 5
1
9
Department's Exam Results
Exam Pass FailExample of Results
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Final Examination Residents 2014
Anesthesiology
Emergency
FamilyMedicine
Obstetricsand
Gynecology
Orthopaedics
Otolaryngology
Pathology Radiology Rehabiltation
Surgery
Max Score 24 26 26 24 27 26 22 25 24 26
Min Score 3 21 20 20 21 21 16 22 23 3
3
21 20 20 21 21 16
22 23
3
24
26 26 24 27 26
22
25 24
26
Department's Score
Min Score Max Score
Example of Results
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2016
5 % Fail
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Shall we start ??
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Types of Bio-medical Research
• Purposes
• Exploratory VS. Confirmatory Research
• Resources
• Laboratory VS. translational VS. Research
• Designs **
• Observational VS. Experimental
• Descriptive VS. Analytic
• Category of clinical question **
• Therapy, diagnosis, causation (risk), prognosis
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Clinical Research
NIH definition :
Research conducted with “human subjects (or on material with human origin)” for which an investigator directly interacts with human subjects
Excluded in Vitro studies that utilized human tissues that cannot be linked to living individual
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Research
Good Question ?
Require Research ?
Methodology ? Population ? Measurement ?
Design
STOP !!!
S T A T I S T I C S
Rethink –Feasibility ?
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8 Steps to do research
• Research questions
• Review & Do literatures search
• Create study design : Protocol writing * (ethic submit)
• Perform Data correction • Select Data base programing : Epidata, XLS, XLSX, SQL
• Design Data base and variables ( Clarify definitions : Variables & Outcomes)
• Data management • Entry, Validating (checking and cleaning)
• Data Analysis
• Results/Conclusion
• +/- Publication
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What research is made of ?
Elements Purposes
Research questions What questions will the study address ? If Answer known well Change Question
Significance ( Background) Why are the questions important? Rational (e.g. Scientific rational) Ease of use/Applications Find gap of improvement/Best Practices/CPGs
Design (Methodology) How is the study structured ? 1. Descriptive 2. Cross-sectional 3. Case-Control 4. Cohort 5. Systematic Review/Meta analysis
Subjects Who are the subjects and how will they be selected ?
Variables What measurements will be made ?
Statistical issues How large is the study and how will it be analyzed ?
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Sample
Population Real Parameters
Parameter
Statistical inference
Statistical Analysis Answer
Infer
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Internal vs. External validity
Description
Selection
Comparison
Bias
Chance
Conclusion
External validity Internal validity
Population
Sample
Study
subject
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The process of clinical research
Research Questions
Study Plan
Conduct Study
Truth in The Study
Findings in The Study
Truth in The Universe
Design Implement
Infer Infer
Hulley SB. Designing Clinical Epidemiology
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How to conduct of Research Question?
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Components of Research question
P opulation being studied
I ntervention (exposure) being studied
C ontrol (comparison) being studied
O utcome being measured
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What are Errors which concern ? “All of steps of Research work should be aware…to
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Errors (Error-Bias) can occur during any stage of a study?
during
• the literature review of the study question
• the selection of the study sample
• the measurement of exposure and outcome
• the analysis of data
• the interpretation of the analysis
• the publication of the results
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What are Errors which concern ?
•Random error (Chance)
•Systematic error (Bias)
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The process of clinical research
Research Questions
Study Plan
Conduct Study
Truth in The Study
Findings in The Study
Truth in The Universe
Design Implement
Infer Infer
Hulley SB. Designing Clinical Epidemiology
Random & Systematic error
Random & Systematic error
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Errors •Random error
•Type I Error (Alpha)
•Type II Error (Beta)
•Systematic error(Bias)
•A Process at any stages of inference tending to produce results that depart systematically from true values.
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Random error
Urine output
Drug doses
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Random error
Urine output
Drug dose
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Urine output
Drug dose
Before After
Random error
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Urine output
Drug dose
Before After
Random error
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Random error
•Small sample size
•High variation in Samples/Subjects
•Measurement errors
• One-time measure ( eg. BP)
• Unreliable measure ( No calibration)
• Too many measurements
• Non-standardized measurement
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80 90
True BP (intra-arterial cannula)
BP Measures (Sphygmomanometer)
Bias
Chance
v v v v v
v v v
v v v
v v
v
v v v
v v
v v
v
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Strategies to reduce random error
• Appropriated sample size (Not largest sample size)
• Measure endpoints in a precise way
• Standardizing aspect of the protocol which impact on patient-to-patient variations
• Collecting data on key prognostic factors
• Choosing a homogenous group of patient
• Choosing the most appropriated design
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H0= uSBP(A) = uSBP(B)
H1= uSBP(A) = uSBP(B)
Statistical Testing In Population Different exist (+)
No Different exist (-)
Different (+) Reject Null Hypothesis
Power 1-Beta
False Positive (alpha)
Type I Error
No-Different (-) Accept Null Hypothesis
False Negative(Beta)
Type II Error
True Negative
1-alpha
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Tool to assess random error
• The P value : A numeric representative of the degree to which random variation alone could account for the difference observed between groups or data being compared, e.g. P < 0.05, P <0.01
• Confidence Interval : Provide a plausible range within which the true association lies and provide all the information in P value and more.
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Bias • The systematic tendency of any factors associated with
the Design Conduct Analysis Interpretation & Conclusion of the result of clinical study to make the estimate of an effect deviate from its true value.
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Bias
• Selection bias should be aware to
• Berkson Bias (Admission bias, hospital admission bias <> Gen population)
• Ascertainment bias (incidence of diseases +/-)
• Healthy worker effect (EGAT Good v.s Poor)
• Volunteer Bias (Healthy or diseases sample e.g. MRI brain)
• Non-Response Bias (eg. Questionnaire sexual issue, confidential issue, not interest issues)
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Bias
•Information bias • occurs in the data collection stage of studies
• “ It happens when estimated effect is distorted either by an error in measurement or by misclassifying the subject for exposure and/or outcome variables.
• Observer bias
• Recall bias esp. case control study
• Reporting bias ( synonym. Self report response bias)
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•Ecological Bias (bias-different environment)
•Confounding Bias (Confound factor->outcome)
•Spectrum Bias ( syn. Case mix bias)
•Publication bias
Bias
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Is an unbiased study ever possible ?
•“ The skill of the…researcher, lies not conducting the perfect study, but in documenting and assessing the likely impact of its perfections.”
Silman A. Epidermiological Studies: A Practical Guide Cambridge University Press 2002
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Reliability
Validity
High
High
low
Low
A B
C D
Bias effect with Reliability and Validity of study
Accuracy
Precision
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Population of patients with condition of interest
Sample
Bias
Chance
Conclusion
Description
Selection
Comparison
Describe Effects
Sample
Internal validity
External validity
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Population of patients with condition of interest
Sample
Bias
Chance
Conclusion
Description
Selection
Comparison
Describe Effects
Sample Sampling Bias
Selection bias
Measurement bias
Confounding bias
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Confounding Factors/Bias • A factors that distorts the true relationship of the study
variables of interest by being related to the outcome of interest
Study factor Outcome
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Confounding Factors • A factors that distorts the true relationship of the study
variables of interest by being related to the outcome of interest
Study factor Outcome
Confounding Factor (Confounder)
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Confounding Factors • A factors that distorts the true relationship of the study
variables of interest by being related to the outcome of interest
Study factor Outcome
Confounding Factor (Confounder)
Smoking
Hot Tea Drinking
CA. Stomach
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Cohort study of subjects & Hot Tea Drinking habits
Hot Tea No Hot Tea
CA Stomach
27 14 41
No CA Stomach
48 67 115
Total 75 81 156
Relative Risk = 2.08
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Cohort study of subjects & Hot Tea Drinking habits
Hot Tea No Hot Tea
CA Stomach
27 14 41
No CA Stomach
48 67 115
Total 75 81 156
Relative Risk = 2.08
Hot Tea
No Hot tea
CA Stomach
1 2 3
No CA Stomach
24 48 72
Total 25 50 75
Relative Risk = 1
Hot Tea
No Hot tea
CA Stomach
26 12 38
No CA Stomach
24 19 43
Total 50 31 81
Relative Risk = 1.34 No association
Smoker Non-Smoker
Confounder
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A Priority criteria of confounder
• Clinically/Scientifically sensible
• Must be a risk factor
• Cannot be an intervening factor
• Must be associated with the exposure in the population (imbalance distribution)
• In analysis, crude estimate not equally to adjusted estimate
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Study Designs
Exposure Outcome
-Etiologic agent -Risk factor -Therapeutic measure -Preventive measure
-Disease -Biochemical change -Pathophysiology -Pathophysiologic change
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Classification of study designs
• Classify by presence of comparison group
• Classify by action of investigator
• Only observe observational study
• Assign intervention Experimental study( Clinical trial)
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Did investigator Assign exposure ?
Experimental Study Observational Study
Random/Allocation ? Comparison group ?
RCT NonRCT
Analytical Study
Descriptive Study
Direction ?
Cohort Study Case control Study Cross-sectional Study
E O O E E = O (Same time)
Yes
Yes
Yes Yes Yes
Yes
No
No
No
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Classification of study design
• Observational study
• Descriptive or case-series
• Case control studies(retrospective)
• Cohort studies(prospective)
• Historical cohort studies(retrospective)
• Experimental study
• Controlled trials
• Studies with no controls
• Systematic Reviews/Meta-analysis
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Hierarchy of evidences
Systematic Reviews
RCT
Cohort Study
Case-Control study
Cross-Sectional study
Case Report
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Logic of Cross Sectional Study
Population
Sample
Case with exposure + ve
Case with exposure - ve
Non-case with exposure + ve
Non-case with exposure - ve
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Cross Sectional Study
• Advantage
• Inexpensive, simple (no follow up)
• No exposure, no drop out
• Disadvantage
• Can establish association but not !!! “ conclusion”
• Can not control confounder
• Recall bias usually present
• Incidence-prevalence bias
• Different sample size among groups
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Exam • Obesity
50
100
20
100
Exercise
Obesity
O+ O-
Ex +
Ex -
Relative prevalence O+ = (50)/(100) / (20)/(100) = 1.67 Association ???
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Logic of Case-Control Study
Population
Sample
Case with exposure + ve
Case with exposure - ve
Non-case with exposure + ve
Non-case with exposure - ve
Non-Disease
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Logic of Case-Control Study
Exposed
Exposed
Non-Exposed
Non-Exposed
Disease/Outcome
No Disease/No Outcome
Time
Direction of study
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Case Control Study
• Advantage
• Quickly and Inexpensive
• Feasible for rare disorder or long term follow up
• May be required fewer subjects
• Disadvantage
• Recall bias
• More effect of confounder
• Difficult to find control group
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Logic of Prospective Cohort Study
Population
Disease
No Disease
Disease
No Disease
Exposure -ve
Exposure +ve
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Expose
Non-Expose
With outcome
With outcome
Without outcome
Without outcome
Time
Direction of study
Prospective Cohort Study
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Expose
Non-Expose
With outcome
With outcome
Without outcome
Without outcome
Time
Direction of study
Retrospective Cohort Study Historical Cohort
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Cohort Study
• Advantage
• Can be matched
• Can be standardized in eligible criteria & outcome assessment
• Can establish temporal association **
• Disadvantage
• Usually expensive
• Hard to blind
• Long follow up period for rare disorder
• Difficult to find controls and confounders
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Population
Sample
Treatment Control
Outcome No-Outcome Outcome No-Outcome
Randomized Control Trial
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Population
Sample
Treatment Control
Outcome No-Outcome Outcome No-Outcome
Randomized Control Trial
Randomization
Blind assessment
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RCT Study
• Advantage
• Confounding and variables can be balance by randomization
• Blinding of subjects, medical staff and investigators are achievable
• Disadvantage
• Cost in term of time and money
• Dropout or loss to follow up are common event
• Need time to final results.
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Types of Bio-medical Research
• Purposes
• Exploratory VS. Confirmatory Research
• Resources
• Laboratory VS. translational VS. Research
• Designs **
• Observational VS. Experimental
• Descriptive VS. Analytic
• Category of clinical question **
• Diagnosis, causation (risk), Therapy , prognosis
If we look as
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The study design for diagnostic test
Patients suspected of
target conditions
Diagnostic test Gold standard
test Target
condition (+/-)
The study for treatment/prevention
1. Random allocation (by chance) : participants to interventions (Randomization)
2. Blind : Double , triple blind….etc 3. Placebo 4. Intention to treat analysis 5. Complete follow up > 80 %
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Accuracy of Test Result
Present (+) Absent (-)
Positive (+) TP a
FP b
Negative(-) FN c
TN d
Disease
Test
a+c b+d
Sensitivity = True positive rate = a/a+c Specificity = True negative rate = d/b+d
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How to choose Sense VS. Specificity ? Sensitivity Specificity
1.The ability of test to identify correctly those who have disease. 2.Use to “rule out” 3.There is a reason to suspect dangerous but treatable condition
SNout
1.The ability of test to identify correctly those who do not have the disease 2.Use to confirm “ Rule in ” 3.Need when false-positive result can harm the patient physically, emotionally or financially.
SPin
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•Anti HIV Positive เป็นจรงิ ๆ หรอืคะ่ ?
•Negative ไมเ่ป็นแน่คะ่
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Risk study (Causation) • Exposure & Outcome
Exposure Outcome
Risk Factors Intervention Maneuver
Disease Health Problems
Independent variable dependent variable
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Cause
• A cause of disease event is an antecedent event , condition, or characteristic that was necessary for occurrence of disease at the moment of it occurred, give that other conditions are fixed (Kenneth J. Rothman)
• Is a statistical relationship between two or more events, characteristics or other variables.
Association
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Causal criteria ( Modified from Bradford-Hill AB)
Temporality
Strength
Dose-response
Consistency
Biological plausibility
Reversibility
Specificity
Analogy
Experimental evidences
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Criteria for judgment of causal associations(Hills’ Criteria)
• Temporal sequence: Did exposure precede outcome?
• Strength of association : How strong is the effect, measured as relative risk or odds ratio?
• Coherence with existing knowledge: Is the association consistent with available evidence?
• Analogy : Is the association similar to others
• Experimental evidence: has a randomized control
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Research Design which assess cause ?
•Cohort study +++
•Case-control +++
•Cross sectional study +
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Other research with prognostic study
• A prediction of future course of diseases following its onset
• A group of patients having something in common are assembled and followed forward in time, and clinical outcomes are measured.
• “ Natural history of disease”
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Onset of Acute MI
Risk Prognosis
Risk Factors Age Male Smoking HT LDL Inactively
Prognostic Factors Age female Smoking Hypotension Anterior infarction CHF Ventricular arrhythmias
Death
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Prognosis
• An inception cohort of persons, all initially free of outcome of interest
• Representative of sample
• Homogenous to prognostic risk
• Objective outcome measurement
• FU >= 80 % of patients
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Broad topics of Research • Diagnosis –Demonstrate that new diagnosis test is
valid/reliable
Preferred “cross sectional study”
• Causation or Risk-Determine that agent is related to development of illness, preferred “Cohort or case-control study”
• Therapy – Testing the efficacy of intervention
preferred “RCT”
• Prognosis- determine what happen to someone with some stage of disease, preferred “Prospective Cohort study”
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Is the exposure or intervention under the control of investigator
Are the subjects followed up over time?
Are the subjects selected according to The outcome ?
Cross sectional Study
Experimental Study
Cohort Study
Case-Control Study
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Key methodological strength and weakness
Design Starting point-Assessment
Strength Frequency of publication
RCT E-O Low susceptibility to bias
Feasibility, generalizability
Cohort E-O Feasible when randomization of exposure not possible
Susceptible to bias, limited validity
Case-Control O-E Overcomes temporal delays, may require small sample size
Susceptible to bias, limited validity
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Certificate of Completion (https://www.citiprogram.org)
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Thank You [email protected] [email protected]