Study Designs - NIIRH

8/8/2019 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

Study Designs - NIIRH

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