02 Study Designs - Research Methodology Workshop - Aug 2011.ppt

Research methodology..Study design guides to choose the appropriate method to proceed the research

1. Study Designs in Clinical ResearchStudy Designs in Clinical Research
an overview..an overview..
Workshop on Research MethodologyWorkshop on Research Methodology
NIRT-NIENIRT-NIE
ChennaiChennai
3-4 August 20113-4 August 2011
Dr. M S JawaharDr. M S Jawahar
Deputy Director (Sr. Gr.)Deputy Director (Sr. Gr.)
National Institute for Research in TuberculosisNational Institute for Research in Tuberculosis
ChennaiChennai

2. Research questionResearch question

Is it relevant?Is it relevant?

Will it fill a gap in knowledge?Will it fill a gap in knowledge?

Has it been done before?Has it been done before?

Is it feasible?Is it feasible?

3. To minimiseTo minimise

Random errorRandom error

Wrong result due to Wrong result due to chancechance

Systemic errorSystemic error

Wrong result due to Wrong result due to biasbias
The goal of clinical researchThe goal of clinical research

4. Clinical research methods…Clinical research methods…

Case reports, case series Case reports, case series

Cross sectional studies (surveys)Cross sectional studies (surveys)

Cohort studiesCohort studies

Case-control studiesCase-control studies

Clinical trialsClinical trials

Qualitative research methodsQualitative research methods

Meta analysisMeta analysis

Systematic reviewsSystematic reviews

5. Type of studies – hierarchy of efficiencyType of studies – hierarchy of efficiency
B
I
A
S
Case series
Cohort Studies
RCT

6. Case reports, Case seriesCase reports, Case series

Collections of reports of individual patients with Collections of reports of individual patients with
the same condition, or of a single patient.the same condition, or of a single patient.

Usually of an unusual problemUsually of an unusual problem

Used to illustrate an aspect of a condition, the Used to illustrate an aspect of a condition, the
treatment or the adverse reaction to treatment.treatment or the adverse reaction to treatment.
Eg: A patient presents with an unfamiliar illness. Eg: A patient presents with an unfamiliar illness.
You would search for case reports that could You would search for case reports that could
help you decide on a direction of treatment or to help you decide on a direction of treatment or to
assist on a diagnosisassist on a diagnosis

7. Study Designs in Clinical Research Study Designs in Clinical Research
Research Design
Descriptive Analytical
Observational ExperimentalSurvey
Cohort Case-ControlRCT Non-RCT

8. Research Design
Descriptive Analytical
Observational ExperimentalSurvey
Cohort Case-ControlRCT Non-RCT
Study Designs in Clinical Research Study Designs in Clinical Research

9. Research Design
Descriptive Analytical
Observational Experimental
Cross-
sectional
Cohort Case-ControlRCT Non-RCT
Study Designs in Clinical Research Study Designs in Clinical Research

10. Research Design
Descriptive Analytical
Observational Interventional
Cross-
sectional
Cohort Case-ControlRCT Non-RCT
Study Designs in Clinical Research Study Designs in Clinical Research

11. Research Design
Descriptive Analytical
Observational Interventional
Cross-
sectional
Cohort Case-ControlRCT Non-RCT
Study Designs in Clinical Research Study Designs in Clinical Research

12. Research Design
Descriptive Analytical
Observational Interventional
Cross-
sectional
Cohort Case-ControlRCT Non-RCT
Study Designs in Clinical Research Study Designs in Clinical Research

13. Temporal profile in observational studiesTemporal profile in observational studies

14. Cross-Sectional StudyCross-Sectional Study

Conducted at a single point in time or over a Conducted at a single point in time or over a
short period of time. No Follow-up.short period of time. No Follow-up.

Exposure status and disease status are Exposure status and disease status are
measured at one point in time or over a period.measured at one point in time or over a period.

Prevalence studies. Comparison of prevalence Prevalence studies. Comparison of prevalence
among exposed and non-exp.among exposed and non-exp.

15. Cross-Sectional StudyCross-Sectional Study

Diseases of slow on-set and long duration.Diseases of slow on-set and long duration.

Conducted over short period of timeConducted over short period of time

Many outcomes can be assessed Many outcomes can be assessed

Relatively inexpensiveRelatively inexpensive

Hypothesis generatingHypothesis generating

Very useful for public health planning Very useful for public health planning
(number of beds in a hospital).(number of beds in a hospital).

16. Cross-sectional Study Cross-sectional Study
DisadvantagesDisadvantages

Difficult to separate cause from effect, because Difficult to separate cause from effect, because
measurement of exposure and disease done at the measurement of exposure and disease done at the
same time. same time.

A person’s exposure status at time of study may A person’s exposure status at time of study may
have little to do with their exposure status at the have little to do with their exposure status at the
time disease began.time disease began.

17. Cohort StudiesCohort Studies

Can either start with group that is exposed or Can either start with group that is exposed or
with a defined population and wait for exposure with a defined population and wait for exposure
to occurto occur

Exposure determined prior to outcomeExposure determined prior to outcome

18. Become Diseased
Remain non-diseased
Become Diseased
Remain non-diseased
Exposed
Non-
Exposed
Incidence
Incidence
Relative
Risk
Cause Effect
Time
P
o
p
u
l
a
t
i
o
n
Cohort Study sequence

19. DiseaseNo diseaseTotal
Exposed a b a+b
Non exposedc d c+d
Total a+c b+d a+b+c+d
Cohort study in a 2 x 2 table
Known at the
beginning of the study

20. Types of cohort studiesTypes of cohort studies
Lancet 2002; 359: 341-45

21. Cohort Studies - advantages Cohort Studies - advantages

Able to determine time sequence between Able to determine time sequence between
exposure & diseaseexposure & disease

Avoids bias in measuring exposureAvoids bias in measuring exposure

Able to study multiple exposures & multiple Able to study multiple exposures & multiple
outcomesoutcomes

Able to calculate incidence of disease in Able to calculate incidence of disease in
exposed and unexposedexposed and unexposed

Good for rare exposuresGood for rare exposures

22. Cohort Studies - disadvantages Cohort Studies - disadvantages

Requires long follow up periodRequires long follow up period

Potential for loss to follow upPotential for loss to follow up

Require large sample sizeRequire large sample size

Inefficient for rare diseasesInefficient for rare diseases

Expensive Expensive

23. Case-Control StudiesCase-Control Studies

Cases: persons with a given diseaseCases: persons with a given disease

Controls: persons without the given disease Controls: persons without the given disease

Ascertain exposure or background of the two Ascertain exposure or background of the two
groups and compare the proportiongroups and compare the proportion

Best suited for study of diseases where Best suited for study of diseases where
medical care usually sought, (hip fracture, medical care usually sought, (hip fracture,
cancer) because this makes it easier to identify cancer) because this makes it easier to identify
casescases

24. Design of case-control studyDesign of case-control study
Cases
Outcome
Exposure
Controls
Time
Exposed
Un-exposed
Odds of
smoking
Odds of
smoking
O
d
d
s

R
a
t
i
o

25. Cases ControlsTotal
Exposed a b -
Non exposedc d -
Total a+c b+d -
Case control study in a 2 x 2 tableCase control study in a 2 x 2 table
Fixed at the
beginning of the study

26. Selection of CasesSelection of Cases

Ideally, investigator enrolls all incident cases in Ideally, investigator enrolls all incident cases in
a defined population in a specified period a defined population in a specified period

Select cases from registries, hospitals, clinicsSelect cases from registries, hospitals, clinics

When all incident cases in a population are When all incident cases in a population are
included, the study is representative; otherwise included, the study is representative; otherwise
there is potential for bias (e.g. referral bias)there is potential for bias (e.g. referral bias)

27. Selection of controlsSelection of controls

Critical that exposure in controls is Critical that exposure in controls is
representative of exposure in the populationrepresentative of exposure in the population

Ideal controls would have same/similar Ideal controls would have same/similar
characteristics as the casescharacteristics as the cases

Matching cases to controlsMatching cases to controls

28. Population-Based ControlsPopulation-Based Controls

Best control group is a random sample of Best control group is a random sample of
individuals from same source population (as individuals from same source population (as
the cases) who have not developed the disease the cases) who have not developed the disease

Population-based controls are the best way to Population-based controls are the best way to
ensure that the distribution of exposure among ensure that the distribution of exposure among
the controls is representativethe controls is representative

29. Hospital ControlsHospital Controls

Most frequently used source Most frequently used source

May not be representative of exposure rates in May not be representative of exposure rates in
target populationtarget population

Use of other ill persons as controls will Use of other ill persons as controls will
provide valid result only if their illness is provide valid result only if their illness is
unrelated to the exposure in question unrelated to the exposure in question

30. Advantages of Hospital ControlsAdvantages of Hospital Controls

ConvenientConvenient

CheapCheap

NumerousNumerous

Avoids non-responseAvoids non-response

31. Use of Multiple ControlsUse of Multiple Controls

Case to control ratio used is usually 1:1Case to control ratio used is usually 1:1

If a study has a small number of cases, If a study has a small number of cases,
increasing the number of controls increasing the number of controls
(maximum 4) increases power of study(maximum 4) increases power of study

32. Advantages of Case Control DesignAdvantages of Case Control Design

Relatively inexpensiveRelatively inexpensive

Good for diseases with long latencyGood for diseases with long latency

Optimal for rare diseasesOptimal for rare diseases

Multiple etiologic factors can be evaluated Multiple etiologic factors can be evaluated

Shorter timeShorter time

Smaller sampleSmaller sample

33. Limitations of Case Control DesignLimitations of Case Control Design

Identifying controls may be difficultIdentifying controls may be difficult

Difficult to determine representativeness of Difficult to determine representativeness of
cases & controlscases & controls

Temporal relationship between exposure & Temporal relationship between exposure &
disease difficult to establishdisease difficult to establish

Prone to recall biasProne to recall bias

34. A Case–Control Study of HIV Seroconversion in A Case–Control Study of HIV Seroconversion in
HCW after Percutaneous ExposureHCW after Percutaneous Exposure
NEJM 1997; 337 (21): 1485-1490NEJM 1997; 337 (21): 1485-1490

Risk of HIV infection after percutaneous exposure to HIV-infected blood is 0.3 Risk of HIV infection after percutaneous exposure to HIV-infected blood is 0.3
percent, but the factors that influence this risk are not well understood. percent, but the factors that influence this risk are not well understood.

MethodsMethods: case–control study of HCWs with occupational, percutaneous exposure to : case–control study of HCWs with occupational, percutaneous exposure to
HIV-infected blood. The cases - those who became seropositive after exposure to HIV-infected blood. The cases - those who became seropositive after exposure to
HIV. The controls were those exposed to HIV but did not seroconvert. HIV. The controls were those exposed to HIV but did not seroconvert.

ResultsResults Logistic-regression analysis based on 33 case patients and 665 controls showed Logistic-regression analysis based on 33 case patients and 665 controls showed
that significant risk factors for seroconversion were that significant risk factors for seroconversion were

deep injury (odds ratio = 15; 95 percent confidence interval, 6.0 to 41), injury with a device deep injury (odds ratio = 15; 95 percent confidence interval, 6.0 to 41), injury with a device
that was visibly contaminated with the source patient's blood (odds ratio = 6.2; 95 percent that was visibly contaminated with the source patient's blood (odds ratio = 6.2; 95 percent
confidence interval, 2.2 to 21), confidence interval, 2.2 to 21),

a procedure involving a needle placed in the source patient's artery or vein (odds ratio = 4.3; a procedure involving a needle placed in the source patient's artery or vein (odds ratio = 4.3;
95 percent confidence interval, 1.7 to 12), 95 percent confidence interval, 1.7 to 12),

exposure to a source patient who died AIDS within two months (odds ratio = 5.6; 95 exposure to a source patient who died AIDS within two months (odds ratio = 5.6; 95
percent confidence interval, 2.0 to 16). percent confidence interval, 2.0 to 16).

The case patients were significantly less likely than the controls to have taken zidovudine The case patients were significantly less likely than the controls to have taken zidovudine
after the exposure (odds ratio = 0.19; 95 percent confidence interval, 0.06 to 0.52). after the exposure (odds ratio = 0.19; 95 percent confidence interval, 0.06 to 0.52).

ConclusionsConclusions The risk of HIV infection after percutaneous exposure increases with a The risk of HIV infection after percutaneous exposure increases with a
larger volume of blood and, probably, a higher titer of HIV in the source patient's larger volume of blood and, probably, a higher titer of HIV in the source patient's
blood. Postexposure prophylaxis with zidovudine appears to be protective.blood. Postexposure prophylaxis with zidovudine appears to be protective.

35. Clinical Trials Clinical Trials

36. Types of Clinical TrialsTypes of Clinical Trials

Phase I – assesses safety, in volunteersPhase I – assesses safety, in volunteers

Phase II – efficacy and safety, in patientsPhase II – efficacy and safety, in patients

Phase III – detailed investigation of efficacy and Phase III – detailed investigation of efficacy and
safety in large number of patientssafety in large number of patients

Phase IV – assessment of post-marketing Phase IV – assessment of post-marketing
surveillancesurveillance

37. The experimental study design, or The experimental study design, or
the clinical trial, is a procedure that the clinical trial, is a procedure that
can provide data of such quality can provide data of such quality
that it most closely resembles the that it most closely resembles the
controlled experiment done by controlled experiment done by
basic science researchersbasic science researchers

38. Ecological studiesEcological studies

Epidemiological studies in which the unit of analysis is a Epidemiological studies in which the unit of analysis is a
population rather than an individual (smoking and lung population rather than an individual (smoking and lung
cancer deaths in different countries). Inferior to cohort cancer deaths in different countries). Inferior to cohort
and case-control studies because it is susceptible to and case-control studies because it is susceptible to
ecological fallacy. ecological fallacy.

Can be confused with cohort studies. The difference is Can be confused with cohort studies. The difference is
that in ecological studies there is no information on the that in ecological studies there is no information on the
individual members of the populations compared (e.g. individual members of the populations compared (e.g.
comparing several states based on state-wide average air comparing several states based on state-wide average air
pollution and state-wide average prevalence of respiratory pollution and state-wide average prevalence of respiratory
diseases); whereas in a cohort study the data pair diseases); whereas in a cohort study the data pair
exposure/outcome is known for each individualexposure/outcome is known for each individual

Can be carried out easily, quickly and inexpensively using Can be carried out easily, quickly and inexpensively using
data that are already available. If interesting and strong data that are already available. If interesting and strong
associations are observed, the results can provide the associations are observed, the results can provide the
opportunity for later, more carefully designed studiesopportunity for later, more carefully designed studies

39. Ecological fallacyEcological fallacy

Fallacy in interpretation of statistical data in an Fallacy in interpretation of statistical data in an
ecological study, where inferences about nature of ecological study, where inferences about nature of
specific individuals are based upon aggregate statistics specific individuals are based upon aggregate statistics
for group. This fallacy assumes that for group. This fallacy assumes that individualindividual members members
have the have the averageaverage characteristics of the group at large. characteristics of the group at large.
However, statistics that accurately describe However, statistics that accurately describe groupgroup
characteristics do not necessarily apply to characteristics do not necessarily apply to individualsindividuals
within that group. within that group.

Stereotypes, which assume that groups are Stereotypes, which assume that groups are
homogeneous, are one form of ecological fallacy. Eg, if homogeneous, are one form of ecological fallacy. Eg, if
a particular group of people are measured to have a a particular group of people are measured to have a
lower average IQ than the general population, it is an lower average IQ than the general population, it is an
error to assume that error to assume that allall members have a lower IQ than members have a lower IQ than
the general population. the general population.

40. Meta-AnalysesMeta-Analyses

A systematic, objective way to combine data from A systematic, objective way to combine data from
many studies, usually from RCTs, and arrive at a many studies, usually from RCTs, and arrive at a
pooled estimate of Rx effectiveness and statistical pooled estimate of Rx effectiveness and statistical
significance.significance.

Can also combine data from case/control and Can also combine data from case/control and
cohort studies. The advantage is that it increases cohort studies. The advantage is that it increases
sample size and allows for analyses that would not sample size and allows for analyses that would not
otherwise be possible.otherwise be possible.

Two problems - publication bias (negative studies Two problems - publication bias (negative studies
often not published) and quality of the design of often not published) and quality of the design of
the studies from which data is pulled the studies from which data is pulled

41. Systematic ReviewsSystematic Reviews

A comprehensive survey of a topic that takes A comprehensive survey of a topic that takes
great care to find all relevant studies of the great care to find all relevant studies of the
highest level of evidence, published and highest level of evidence, published and
unpublished, assess each study, synthesize unpublished, assess each study, synthesize
the findings from individual studies in an the findings from individual studies in an
unbiased, explicit and reproducible way and unbiased, explicit and reproducible way and
present a balanced and impartial summary present a balanced and impartial summary
of the findings with due consideration of of the findings with due consideration of
any flaws in the evidence.  any flaws in the evidence.  

42. More rigorous than a traditional literature reviewMore rigorous than a traditional literature review

Clearly formulated research questionClearly formulated research question

Published & unpublished literature searchedPublished & unpublished literature searched

Identified research is assessed according to an explicit Identified research is assessed according to an explicit
methodologymethodology

Results of critical assessment of studies combinedResults of critical assessment of studies combined

Final results placed in context, addressing issues such Final results placed in context, addressing issues such
as quality of studies, impact of bias & applicability of as quality of studies, impact of bias & applicability of
findingsfindings
The difference between a systematic review and meta-The difference between a systematic review and meta-
analysis is that a systematic review looks at the whole analysis is that a systematic review looks at the whole
picture (qualitative view), while a meta-analysis looks picture (qualitative view), while a meta-analysis looks
for specific statistical picture (quantitative view). for specific statistical picture (quantitative view). 
Systematic ReviewsSystematic Reviews

43. SummarySummary

Clinical research maybe observational or Clinical research maybe observational or
experimentalexperimental

Experimental trials maybe randomised or non-Experimental trials maybe randomised or non-
randomisedrandomised

Observational studies maybe descriptive (no Observational studies maybe descriptive (no
comparison group) or analytical (with comparative comparison group) or analytical (with comparative
group)group)

Analytical studies may be prospective (cohort) or Analytical studies may be prospective (cohort) or
retrospective (case-control)retrospective (case-control)

Descriptive studies cannot investigate associations as Descriptive studies cannot investigate associations as
exposure and outcome are measured at the same exposure and outcome are measured at the same
timetime