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Types, Architecture and Hierarchy of

Research Studies
Abdel-Hamid Serwah, MD
Professor of Internal Medicine
astroenterolo!y
"linical #pidemiolo!y $nit, %&M, S"$, #!ypt
'()* - )+*+
Objectives of the talk

To identify the types and architecture of different study


designs.

To identify the hierarchy of study designs

To Address the applications of each type

To identify the pluses and minuses of each type

Are All Types of research studies


ali,e-

May any one study type replace


the others-
Some Research Questions?
oes obesity have bad effects on health?
!s "eight reduction beneficial?
!s #$% better than the called traditional learning?
!f you met "ith a strange or ne" phenomenon& ho" do you deal "ith?
'ongenital anomalies and drugs given during pregnancy?
!s the ne" discovered drug better than the available one?
Are smokers at higher risk for (rare cancers) than non smokers?
!s *# carcinogenic?
Types and *ierarchy of Study esigns
escriptive

'ase report

'ase series

Survey
Observational
Analytic
Observational

'orrelational

'ross sectional

'ase+control

'ohort studies
,-perimental

Randomi.ed
controlled trials
Strength of evidence for causality between a risk factor and outcome
Other Studies:
Systematic review
Meta analysis
Cross over
N of 1 trial
Descriptive studies

Describing a novel phenomena

Case reports or case series

Cisapride associated arrhythmias

Sildenafil-associated ischemic optic neuropathy.

HP associated Maltoma

Getting a lay of the land

Surveys

- Prevalence of H!"#DM in certain population$


- %&areness
Descriptive studies

Still play an important role in describing trends


and generating hypotheses about novel
associations

Cannot establish causal relationships


'ase Series

/hat are they?

Author describes some interesting or intriguing observations


that occurred to a small number of patients

'haracteristics0

escriptive

The simplest design

%ead to hypotheses subse1uently investigated by other types


2'ase+'ontrol& 'ross+Sectional or 'ohort study3

4enerally over short period of time

4enerally no controls
"ase Series . "ase Reports
Observational / Analytic Studies
'ross Sectional
'ase+'ontrol
'ohort
,-perimental
5o+o-perimental
Attempt to establish a causal link bet"een a
predictor6risk factor and an outcome.
Cross-sectional Study'

escriptive value0

*o" many 7niversity students smoke?

/hat is the age and se- distribution and school year of


7ni. students "ho smoke?

Analytic value0

!s there an association bet"een regular smoking and test


scores among 7ni. students?

7nivariate

8ultivariate 2controlling for (confounders)3


'ross+sectional Study0 Advantages

Yields Prevalence (not incidence)

Relatively Fast and Inexpensive - no waitin!

"o loss to #ollow up

Associations can be studied

$ay study several outco%es

&ontrol over %easure%ents

&an be used to assess prora%s (Pre/Post study)


'ross+sectional study0 isadvantages

Provides only a snaps'ot in ti%e

&annot deter%ine causality

(oes not yield incidence)

Potential bias in %easurin exposure)

&annot study rare outco%es


Cross-sectional study'
Disadvantages
time
- Cannot determine causality
Heart diseases
Smoking
Measures of association
Disease (Outcome)
Yes No
Risk
Factor
(Exposure)
Yes A
No C D
Risk ratio
(relative risk)
A
A !
C
C ! D
Risk ratio
(relative risk)


(hat if )are Cases$

Congenital anomalies in relation to


drugs given during ppregnancy .

)is* factors of rare cancers#


diseases
Case Control Study
Structure of "ase "ontrol Studies
Data
Analysis
Outcome
!"osure
Case Selection
+ Case definition
, e.g. lung cancer confirmed by biopsy
-ncident cases'

+ )ecruit ne& cases at time of disease occurrence

+ .etter for ma*ing inference about association


bet&een ris* factor and developing the disease
Prevalent vs. incident cases

, Prevalent'
+ )is* factors may be more related to survival &ith
disease than development /incidence0 of disease

+ -f many people die soon after diagnosis1 may over-


represent long term survivors
,
Selecting Cases /cont.0

!ncident cases are preferable to prevalent cases for


reducing0

recall bias and

over+representation of cases of long duration

The most desirable "ay to obtain cases is to include all


incident cases in a defined population over a specified
period of time
Selection of 'ontrols0 Sources

The controls should be dra"n from the population of "hich


the cases "ere recruited.

Sampling 9rames for selection of controls0


+ #opulation of an administrative area
-
*ospital patients
-
Relatives of cases 2spouses : siblings3
-
Associates of the cases 2neighbors& co+"orkers& etc3
Sources of cases and controls in 'ase 'ontrol Studies
Controls Cases
;Sa%ple o# eneral population
;"on-cases in a sa%ple o# t'e
population
;All cases dianosed in t'e
co%%unity
;All cases dianosed in a sa%ple
o# t'e population
;Sa%ple o# patients in all
'ospitals w'o do not 'ave
t'e disease
;Sa%ple o# patients in t'e sa%e
'ospital w'o do not 'ave t'e
disease
;All cases dianosed in all
'ospitals (or in sinle *))
;Spouses+ siblins or associates
o# cases
;Any o# t'e above %et'ods
#atients0 Sources of !nformation on ,-posure
Sources of information on e2posure'
Patients
parents' in children or severe illness.
)elatives1
Hospital records1
3mployment records1 etc.
(hen information is obtained via
intervie&s1 recall bias is often a concern.
Measure of Association in "ase
"ontrol Studies
Data
Analysis
8easures of association in case control
Studies
Disease Status
Case Control
Exposure
Yes A
No C D
Odds ratio
A , (
-------
. , &
Odds Ratio 2OR3

A ratio t'at %easures t'e c'ance or li/eli'ood o#


exposure #or cases co%pared to controls

Odds o# exposure 0 nu%ber exposed nu%ber


unexposed

OR "u%erator1 Odds o# exposure #or cases

OR (eno%inator1 Odds o# exposure #or controls


233 433 5otal
442 66
"on-s%o/er
789 774 S%o/er :xposure
Status
"o &*(
(&ontrols)
&*( cases
(&ases)
(isease Status
,-amples0 'alculating the Odds Ratio
Odds Ratio 0 0
A(
.&
774 x 442
789 x 66
0 7)94
!nterpreting the Odds Ratio
5'e odds o# exposure #or cases are 7)94 ti%es t'e
odds o# exposure #or controls)
5'ose wit' &*( are 7)94 ti%es %ore li/ely to be
s%o/ers t'an t'ose wit'out &*(
433 433
5otal
773
23 "o Alco'ol
;3 793
Alco'ol
:xposure
Status
"o &ancer &ancer
(isease Status
Alcohol 'onsumption and %aryngeal 'ancer
Odds Ratio
0 0
A(
.&
793 x 773
;3 x 23
0
2)6;
The odds of alcohol consumption are <.=> times greater among
those "ith laryngeal cancer than among those "ithout cancer.
OR"# OR$# OR%#
Odds o#
exposure
#or cases are
reater t'an
t'e odds o#
exposure #or
controls
Odds o#
exposure are
e<ual a%on
cases and
controls
Odds o#
exposure #or
cases are less
t'an t'e odds
o# exposure #or
controls
Odds
co%parison
between cases
and controls
:xposure
increases
disease ris/
(Ris/ #actor)
Particular
exposure is not
a ris/ #actor
:xposure
reduces disease
ris/ (Protective
#actor)
:xposure as a
ris/ #actor #or
t'e disease=
ORs& #+?alues and >@A '!s for 'ase+'ontrol Study
"ith B ifferent Sample Si.es
Sample Si&e
Para%eter
&o%puted n043 n0>3 n0>33
OR C.D C.D C.D
p-value D.@DD D.CDD D.DDE
;>? &Is D.@+F.F D.>+<.F E.@+ C.G
Strent's o# t'e &ase-&ontrol Study
8ost efficient design for rare diseases
!t shortens the "aiting time re1uired by cohort studies
'an be used "hen R'T is not logistically or ethically
feasible.
,fficient& 1uick and easy& cost effective& fe"er practical
restrictions
Re1uires a smaller study population than a cohort study
'an establishes an association 2Odds Ratio3
7seful for generating hypotheses 2multiple risk factors can
be e-plored3.
'an not prove causality because of0
7ncertainty of e-posure+disease time relationship
The e-istence of confounding factors
5ot efficient for studying rare e-posures
Subject to biases 2recall : selection bias&
misclassification3
isadvantages of 'ase+'ontrol Studies
Correlation and
)egression
Correlation and )egression
"orrelation
What type of reIationship exists between the two
variabIes and is the correIation significant?
x
y
Cigarettes smoked per day
Score on SAT
Height
Hours of Training
ExpIanatory
(Independent) VariabIe
Response
(Dependent) VariabIe
A quantitative reIationship between two intervaI or ratio
IeveI variabIes
Number of Accidents
Shoe Size Height
Lung Capacity
Grade Point Average
IQ
"orrelation

Measures and describes the stren!th and


direction of the relationship

/i0ariate techni1ues re1uires two 0ariable


scores from the same indi0iduals 2dependent
and independent 0ariables3

Multi0ariate when more than two


independent 0ariables 2e4! effect of
ad0ertisin! and prices on sales3

5ariables must be ratio or inter0al scale


Negative Correlationas x increases, y
decreases
x = hours of training (horizontal axis)
y = number of accidents (vertical axis)
Scatter Plots and !ypes of Correlation
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20
Hours of Training
A
c
c
i
d
e
n
t
s
Positive Correlationas x increases, y increases
x = !" score
y = #P!
#
P
!
Scatter Plots and !ypes of Correlation
$%&&
'%()
'%)&
'%&&
*%()
*%)&
*%*)
*%&&
+%)&
+%()
'%*)
'&& ')& $&& $)& )&& ))& ,&& ,)& (&& ()& -&&
.ath !"
No linear correlation
x = height y = /0
Scatter Plots and !ypes of Correlation
+,&
+)&
+$&
+'&
+*&
++&
+&&
1&
-&
,& ,$ ,- (* (, -&
Height
I
Q
Strong' negati(e relations)ip
*ut non-linear+
Scatter #lots and $y"es of
Correlation
Correlation Coefficient r
! measure of the strength and direction of a linear
relationshi2 bet3een t3o variables
"he range of r is from + to +%
/f r is close to +
there is a strong
2ositive
correlation%
/f r is close to + there
is a strong negative
correlation%
/f r is close to &
there is no linear
correlation%
+ &
+
&utliers44444
Outliers are dangerous
Here ,e )a(e a spurious
correlation o- r$./01
,it)out 23' r$./41
,it)out 23 5 6E'
r$./7#
The correlation coefficient of number of times absent
and final !rade is r 6 7(489:4 The coefficient of
determination is r' 6 27(489:3' 6 (48:(;4
Interpretation< About 8:= of the 0ariation in final !rades
can be e>plained by the number of times a student is
absent4 The other := is une>plained and can be due to
samplin! error or other 0ariables such as intelli!ence,
amount of time studied, etc4
Strengt) o- t)e Association
The coefficient of determination, r', measures
the stren!th of the association and is the ratio
of e>plained 0ariation in y to the total 0ariation
in y4
Cohort study

"on-32perimental

32perimental
Prospective1 longitudinal1 follo& up
Studies' Cohort

A cohort study is a0

'omparative

Observational6 analytic study

Subjects are grouped by their e-posure status

All subjects& are follo"ed for"ard in time to determine


if one or more ne" outcomes 2diseases3 occur

The rates of disease incidence among the e-posed and


une-posed groups are determined and compared.
Architecture of 'ohort studies
,lements of a cohort study

Selection of sample from population

8easures predictor variables in sample

9ollo" population for period of time

8easure outcome variable

Famous cohort studies


9ramingham
5ursesH *ealth Study 25*S3
/omen health !nitiative 2/*!3
#hysiciansH *ealth Study
"ohort studies< Marchin! towards outcomes
Lancet *&&*4 359: '$+-$)
"he defining characteristic of all cohort studies is that the5 trac6 2eo2le for3ard in
time from exposure to outcome% 7ata collection ma5 be 2ros2ective or
retros2ective% Ex. Contraceptives and DVT%
"ohort studies< marchin! towards outcomes
Exposed subjects
Unexposed subjects
CIassic (Concurrent)
Cohort Study
Disease
Disease
Today + 5 - 5 - 10 + 10
HistoricaI
(Non-concurrent)
Cohort Study
Exposed subjects
Unexposed subjects
Disease
Disease
"ime in 8ears
Today + 5 - 5 - 10 + 10
"ime in 8ears
Cohort Study' Design 4utlines
:xperi%ental Studies1 &ontrolled trials

,-perimental drug or procedure compared


"ith another& "ith a placebo& or "ith the
standard procedure.
Structure o# R&5 Studies
,-amples of 'ohort
Studies
Schematic 4utline of Study
Design
)C!' )esearch 5uestion
%s Mass treatment of sc&isto' more effective t&an
treatment of "ositive cases after stool analysis(
Mass !reatment 6s. Stool analysis and treatment
of 7ve Cases
Study #o"ulation
5urseHs *ealth Study 25*S3
5one-perimental esign

Individuals classified according to "hether they


received *ormonal Replacement Therapy 2*RT3& or
not

Subjects "ere follo"ed for various health outcomes0

heart attacks

strokes

breast cancer and so on.


Example of publication0 Stampfer& 8.& 'oldit.& 4.& /illett& /.& 8anson& I.& Rosner& $.& Spei.er& 9.& et al. 2E>>E3.
#ostmenopausal estrogen therapy and cardiovascular disease. Ten+year follo"+up from the nursesJ health study. New
England Journal of Medicine, 3252EE3& F@G+FGC.
5urseHs *ealth Study 25*S3 5on+
e-perimental esign
8Healt) outcomes8 )eart attacks' strokes' *reast cancer and so on/
/omenHs *ealth !nitiative 2/*!30 ,-perimental esign

!he (H- study randomly assigned about half its sub9ects


to'
- Group :' that received hormone replacement
therapy /H)!0.
- Group ;. received an identical loo*ing placebo.

%ll Sub9ects &ere follo&ed for <= years to ascertain various health
outcomes'
>Heart attac*s
>Stro*es
>.reast cancer and so on.
/riting 4roup for the /omenJs *ealth !nitiative !nvestigators. 2CDDC3. Risks and benefits of estrogen plus
progestin in healthy postmenopausal "omen0 principal results from the /omenJs *ealth !nitiative
randomi.ed controlled trial. JAMA, 2882B3& BCE+BBB.
/omenHs *ealth !nitiative 2/*!3
,-perimental esign 2R'T3
Healt) outcomes8 )eart attacks' strokes' *reast cancer and so on/
'omparison of /*! and 5*S

$oth analy.ed relationships bet"een *RT 2e-planatory


variable3 and various health outcomes 2response
variables3

/*! investigators assigned the e-posure 2*RT3


e-perimental

5*S investigators measured the e-posure but did not assign it


non+e-perimental 2observational3
,ffect of 5icotine on cessation of Smoking
Source: JAMA 1994;271:595-600

32planatory variable' "icotine or placebo patch

?@ sub9ects /A@ in each group0

)esponse variable # outcome' Cessation of


smo*ing /yes#no0
Random
Assignment
4roup E
BD smokers
Treatment E
5icotine #atch
4roup C
BD smokers
Treatment C
#lacebo #atch
Yes
No
Yes
No
%nalysis of )C!

%nalyBed li*e cohort study &ith ))

-ntention to treat analysis C-!!D

Most conservative interpretation

-nclude all persons assigned to


intervention group /including those &ho
did not get treatment or dropped out0

Subgroup analysis

Groups identified pre-randomiBation


Measures of Risk in (cohort Study)
Response to treatment
treatment
Rx 1
Yes
No
Rx 2
a
b
c d
a + c b + d
a + b
c + d
response rate
a
a + b
;
c
c + d
a
ReIative risk:
a + b
c
c + d
,thics of ,-perimental Studies

,1uipoise + balanced doubtK canHt intentionally


e-pose subjects to harm or "ithhold benefit

!nformed consent0 subjects must be a"are of study


objectives

$eneficence0 must provide overall benefit to society

5on+malefficience 2onHt do harm3

Take care0 donHt deprive patients from kno"n


effective treatment
Strengths of cohort studies

Some evidence of causality. Lno" that predictor variable


"as present before outcome variable occurred

irectly measure incidence of a disease outcome

'an study multiple outcomes of a single e-posure 2RR is


measure of association3

Smoking

'?

'a lung

'a esophagus
/eaknesses of cohort studies

,-pensive

!nefficient for studying rare outcomes

'ong. Anomalies and drug during pregnancy

'a pancreas and smoking

Often need long follo"+up period or a very large population


'AR!A

%oss to follo"+up& cross over can affect validity of findings

9ramingham
Problems &ith cohort studies
Selection 2patients6control3 bias
Attrition 2rop out3
'o intervention
'ross over
8isclassification bias
'onfounders
!nformation bias
Recall bias
!ntervie"ers
#ublication bias
*o" to guard against and deal "ith problems?

!horough identification of cases and


controls

)andomiBation in )C!s

.lindness in )C!s

Ese intention to treat analysis -!!


Temporal direction of study desi!ns
Lancet )**)+ 9:;8 ,-./1
4ther Study !ypes
Systematic Re0iews .Meta-
analyses
Study Pyramid
9est
Worst
0rimes DA and Sc&ul1 23 )**)' An overview of clinical researc&' 4ancet 5,67,-./1'
3pidemiologic study designs
?hat type of study to chose depends on<

&hat is the research Fuestion# ob9ective

!ime available for study

)esources available for the study

Common#rare disease or production problem

!ype of outcome of interest

5uality of data from various sources

4ften there are multiple approaches &hich &ill all &or*

Choosing an established design gives you a huge head


start in design1 analysis and eliminating biases
Class 32ercises
- ?hat Type of Research Desi!n-
- Identify e>posure 2Study factors3
- Identify outcome factors 20ariables3
#>ercise @)
Cryptosporidiosis is an enteric illness that is
freFuently &aterborne.
Ghala*dina and colleagues /;@@A0 could find no
published studies of the ris* factors for
cryptosporidiosis in immunocompetent adults.
Patients &ith cryptosporidiosis &ere recruited from a
surveillance system1 and age-matched controls &ere
recruited by random-digit dialing.
Sub9ects in both groups &ere intervie&ed by
telephone to obtain information about previous
e2posures
(hat is the Study Design$
Calvert EL, Hou!to" LA, Coo#er $, et al% Lo"-ter&
'&#rove&e"t '" (u"ct'o"al )y*#e#*'a u*'"
!y#"ot!era#y% +a*troe"teroloy 2002; 12,: 177---5%
.%CGG)4E"D H %-MS' (e have sho&n hypnotherapy /H!0 to
be effective in irritable bo&el syndrome1 &ith long-term
improvements in symptomatology and Fuality of life /54I0.
!his study aimed to assess the efficacy of H! in functional
dyspepsia /JD0.
M3!H4DS' % total of :;? JD patients &ere randomiBed to H!1
supportive therapy plus placebo medication1 or medical
treatment for :? &ee*s.
Percentage change in symptomatology from baseline &as
assessed after the :?-&ee* treatment phase /short-term0 and
after =? &ee*s /long-term0 &ith ;? H!1 ;K supportive therapy1
and ;L medical treatment patients completing all phases of
the study. 54I &as measured as a secondary outcome.
(hat is the Study Design$
.!o&a* SH, S'le" /% E((ect o" )'a"o*t'c e(('c'e"cy o(
a"ale*'a (or u")'((ere"t'ate) a0)o&'"al #a'"% 1r J
Sur 200,; 90:5-9%
!he Fuestion of &hether it is safe to provide analgesia for
patients &ith undifferentiated acute abdominal pain is mar*ed
by longstanding controversy over the possible mas*ing of
physical findings.
!he goal of this revie& is to assess the pertinent studies.
% Medline search &as performed in %pril ;@@;1 using the terms
ManalgesiaM1 Mabdominal painM1 Macute abdomenM and MmorphineM.
4ther articles &ere identified using the bibliographies of papers
found through Medline.
%ll articles reporting clinical trials of analgesia and its effects on
diagnosis or physical e2amination &ere revie&ed.

% revie& that is conducted


according to clearly stated1 scientific
research methods1 and is designed to
minimiBe biases and errors inherent
to traditional1 narrative revie&s.
Margaliot1 Nvi1 Gevin C. Chung. Systematic )evie&s' % Primer for Plastic Surgery
)esearch. P)S Oournal. :;@#P /;@@P0
(hat is a Systematic )evie&$
(hat is the significance of
Systematic )evie&s$

!he large amount of medical literature reFuires clinicians


and researchers ali*e to rely on systematic revie&s in
order to ma*e an informed decision.

Systematic )evie&s minimiBe bias. % systematic revie&


is a more scientific method of summariBing literature
because specific protocols are used to determine &hich
studies &ill be included in the revie&.
Gevin C. Chung1 MD1 Patricia .. .urns1 MPH1 H. Myra Gim1 ScD1 Clinical Perspective' % Practical Guide to Meta-%nalysis. !he Oournal
of Hand Surgery. 6ol. A:% "o.:@ December ;@@?. p.:?P:
Meta- %nalysis

Meta-analysis is a statistical
techniFue for combining the results
of independent1 but similar1 studies
to obtain an overall estimate of
treatment effect.
Margaliot1 Nvi1 Gevin C. Chung. Systematic )evie&s' % Primer for Plastic Surgery
)esearch. P)S Oournal. :;@#P /;@@P0 p.:QK@
Meta- %nalysis /cont.0
(hile all meta-analyses are based on
systematic revie& of literature1 not all
systematic revie&s necessarily include
meta-analysis.
Margaliot1 Nvi1 Gevin C. Chung. Systematic )evie&s' %
Primer for Plastic Surgery )esearch. P)S Oournal. :;@#P /;@@P0
p.:QK@
Junnel Plot
8A funnel "lot is used as a way to assess "u9lication
9ias in meta.analysis':
% Jorest Plot

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