study designs - niirh
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Study designs
S Kannan, D.M (Clinical Pharmacology)
Senior Resident
Department of Clinical PharmacologySeth GS Medical College & KEM hospital
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Making decisions
Diagnosis
Clues (symptoms, signs, tests)
Books, teaching, scientific articlesWe all read a numberof papers
Is one study betterthan the other?
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We are all in a bind
Pressure on time
Staying abreast of published literature
Inverse relationship between knowledge ofcontemporary care and time sincegraduation
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What do we do?
Compulsory hours per year of CME
Failed to improve patient care
Self directed learning Not easy to understand
Scientific illiteracy is a major failing of
medical education
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Study design depends on the research question:the FINER Criteria, Hulley and Cummings, 1998
F - Feasible
I - Interesting
N - Novel
E - Ethical
R - Relevant
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Two categories
Observational Experimental
Comparison group
Descriptivestudy
No Yes
Analyticalstudy
No intervention Intervention
Random allocation
No
Nonrandomisedcontrolled trial
Yes
Randomisedcontrolledtrial
Cross sectional, case control. cohort
Time
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Descriptive studies are the firstforay into research
Describe the frequency, natural historyand determinants of a disease
Case reports/case series/Surveillance Do not allow assessment of association
Follow up with analytical and randomised
controlled studies
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What should descriptive studies tell us
Who has the disease?
What is the condition or disease beingtested?
Why did the condition arise?
When is the condition common or rare?
Where does or does not the diseasearise?
So what?
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First report of AIDSMMWR, June 5 1981
PneumocystisPneumonia --- Los Angeles
In the period October 1980-May 1981, 5 young men, all activehomosexuals, were treated for biopsy-confirmed Pneumocystis cariniipneumonia at 3 different hospitals in Los Angeles, California. Two of thepatients died. All 5 patients had laboratory-confirmed previous or currentcytomegalovirus (CMV) infection and candidal mucosal infection. Casereports of these patients follow.
Patient 1: A previously healthy 33-year-old man developed P. cariniipneumonia and oral mucosal candidiasis in March 1981 after a 2-monthhistory of fever associated with elevated liver enzymes, leukopenia, andCMV viruria. The serum complement-fixation CMV titer in October 1980was 256; in may 1981 it was 32.* The patient's condition deteriorateddespite courses of treatment with trimethoprim-sulfamethoxazole(TMP/SMX), pentamidine, and acyclovir. He died May 3, and
postmortem examination showed residual P. cariniiand CMVpneumonia, but no evidence of neoplasia.
Patient 2: A previously healthy 30-year-old man developed p. cariniipneumonia in April 1981 after a 5-month history of fever each day and ofelevated liver-function tests, CMV viruria, and documentedseroconversion to CMV, i.e., an acute-phase titer of 16 and a
convalescent-phase titer of 28* in anticomplement i
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Lipoatrophy/Lipodystrophy associated withantitretroviral drugs
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Cross sectional studySnapshot in time
Disease and exposure at a particular time
Difficult to judge a temporal relationship
Prevalence study/frequency survey
In women with arthritis, obesity is more common
Obesity Arthritis due to load on the joints
Arthritis Obesity due to reduced mobility
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Cohort studiesMarching towards outcomes
Military word Track people forward in time from exposure
to outcome Compares the experience of a group
exposed to one factor to a group not exposedto the factor
Smokers Vs non smokers Lung cancer
Oral cancer Heart disease Stroke COPD
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Enables calculation of incidence, relativerisks and attributable risks
Selection bias
Not good Rare events
Events that take a long time to develop
Loss to follow up Differential losses between groups can lead to
bias
Alteration of exposure status over time
Cohort studiesMarching towards outcomes
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Case Control studyThinking backwards
Start with the outcome and go back in time toexposure
Cause of AIDS
Identified risk groups Gay men
Blood transfusion recipients
IV drug users
Multiple sexual partners
Not using condoms
Results obtained quickly and at a low cost and effort
Odds ratio
Good for rare outcomes
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Not good
If the frequency of the exposure is low
Affected by Selection of the case group
Selection of the control group
Recall bias Bias from those who gather data
Confounders
Case Control studyThinking backwards
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A research question
Is paracetamol intake associated with anincreased risk of asthma?
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Association between paracetamol use in infancy and asthma at 6-7 years of life
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Paracetamol and asthma:Case control study
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Weekly Vs less than weekly use of paracetamol
Eur Res J, 2008
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Eur Res J, 2008
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Meta-analysis for other pain killers
Eur Res J, 2008
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Is there a biological plausibility?
Paracetamol reduces the amount ofglutathione in the lungs and this mayreduce its antioxidant defense
mechanisms
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Barriers to valid evidence:What Is The Truth Here?
WHAT ABOUT CONFOUNDERS?
IS THERE A BIAS?
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3 key study designs
Time
Exposure Outcome
OutcomeExposure
Cohort study
Case control study
Exposure
Outcome
Cross sectional study
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Nested case control study
Within a cohort
Compare characteristics between casesand controls within a cohort
Blood samples for inflammatory markers forCRP between smokers and COPD cases Vssmokers who did not develop COPD (controls)
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Non randomized controlled trial
Comparison of 2 different cholecystectomysurgical procedures in 2 units in the samehospital
Randomize alternate patients to the 2interventions
May overestimate the advantages of one
Differences in the populations studied
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Randomized controlled studiesGold standard
Equal chance of being allocated to either ofthe 2 groups
Minimize the effects of chance orcoincidence
Minimize biases
Balance confounders
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Types of RCTs
Parallel
Cross over
Factorial
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Aspirin and asthma:Randomized double blind study
37,270 womenassigned to aspirin or
placebo 872 in he ASP group
and 963 in theplacebo group
developed asthma
Thorax, 2008
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Combination Therapy in BPHProvides Dual Mechanism of Action
Alphablockade
5-reductaseinhibition
Dynamiccomponentand irritativesymptoms
Static componentand obstructive
symptoms
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Rationale for Combination Therapy
Alpha1-adrenergic
blockers
Rapidly relievesymptoms
Combination therapy: arrest disease progressionand rapidly relieve symptoms?
5ARIs
Arrest diseaseprogression
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Medical Treatment Of Prostate SymptomsPrimary Research Question
To Determine if Medical Therapy Preventsor Delays the Clinical Progression of BPHas defined by one of the following:
Acute urinary retention (AUR) Renal insufficiency due to BPH (> 50% rise in
baseline serum creatinine & > 1.5 mg/dl)
Recurrent UTI or urosepsis
Incontinence (socially unacceptable) 4 - Point Rise in Baseline AUA Symptom
Score confirmed within 2 - 4 weeks
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Study Design: Overview
Double-blind, placebo-controlled, multicenter, randomizedAverage follow-up: 4.5 years
AUA=American Urological Association; Qmax=maximum urinary flow
Adapted from Bautista OM et al Control Clin Trials2003;24:224-243.
Randomized
N=3047
Entry Criteria Men50 years of age AUA symptom score 830 Qmax 415 ml/sec Voided volume125 ml
Doxazosin(n=756)
Finasteride(n=768)
Finasteride +doxazosin
(n=786)
Placebo(n=737)
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PercentwithEvent
Years from Randomization
Cumulative Incidence of BPH Progression
p < 0.0001 ; df = 3
0
5
10
15
20
25
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Placebo FinasterideDoxazosin Combination
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Cross over trials
Each patient serves as his own control.
Each patient gets both drugs; the order in whichthe patient gets each drug is randomized.
Avoids between participant variation inestimating the intervention effect.
Requires a small sample size.
Assumptions: The effects of intervention during the first period does
not carry over into the second period.
Internal and external factors are constant over time.
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SFC WO TIOWO TIO + SFC
2 weeks 2 weeks 2 weeks 2 weeks 2 weeks
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Factorial design
Used when there are two or moreinterventions.
Allows effects of one intervention to beestimated at all the levels of the otherintervention.
Allows the study of interactive effects of
two interventions
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Effects of Tiotropium, PR and thecombination in COPD
Tiotropium+
Pulmonaryrehabilitation
Placebo+
Pulmonaryrehabilitation
Tiotropium Placebo
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When is an RCT not appropriate?
Aetiology or natural history of disease
Placebo group in an RCT
When it is unethical to randomise
When the effect of an intervention is sopowerful that a trial is not necessary
C l ti I id f BPH P i Pl b
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Percentwit
hEvent
Placebo FinasterideDoxazosin Combination
Years from Randomization
Cumulative Incidence of BPH Progression: Placebo
0
5
10
15
20
25
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
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Limitations/Drawbacks of RCTs
Expensive and time consuming
May not always apply to the generalpopulation (poor external validity)
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Withdrawal designs
Stopping ICS in a group of COPD patientsVs continuing them raises the risk ofexacerbations
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Example of cholesterol and heart disease
500 patients admitted to a hospital with heartattacks
Compare the cholesterol levels of the patientswith heart attacks with those of their neighbours.
Follow up a group of patients with highcholesterol vs normal or low cholesterol.
Randomized treatment of a cholesterol loweringdrug with that of placebo using heart attacks asan end point
Descriptive study
Case control study
Cohort study
Randomized controlled study
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Hierarchy of evidence
Case reports/series
Case control studies
Cohort studiesRandomized controlled trial
Quality of evidenceStrength of recommendations
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Study of nutrient deficiencies in childrenamong a slum population of Mumbai
Study of risk factors for glaucoma
Efficacy and safety of Moxifloxacin, afourth generation quinolone inTuberculosis
Change in mortality after introduction ofantiretroviral drugs among HIV infectedindividuals