101

Ra$onale
Whydoresearch?
Whydoclinicalresearch?
Whynotbenchresearch?
Howtotranslatefrombenchtobedside?
2
Outline
Deningresearchques$ons
Searchingliterature
Causalinference
Studydesigninclinicalresearch
Measurement
Databasemanagement
Somebiosta$s$cs
3
Deningresearchques$ons
PICO(S)inEBM
Popula$on(pa$ent):
HowwouldIdescribeagroupofpa$entssimilartomine?
Interven$on(therapy):
Whichmain/newinterven$onamIconsidering?
Comparison:
Whatisthealterna$vetocomparewiththeinterven$on?
placebo,standardofcare,etc.
Outcome:
WhatcanIhopetoaccomplish,measure,improve,oraect?
Studydesign
Whatstudydesignwouldprovidethebestlevelofevidenceforthis
ques$on?
4
Deningresearchques$ons
PICO(S)indiagnos$c/prognos$cstudy
Popula$on
Whatarethecharacteris$csofthepa$ents/cohort?
Whatisthecondi$onthatmaybepresent?
Interven$on(diagnos$ctest/predictor[s])
Whichdiagnos$ctestamIconsidering?
Comparison
Whatisthediagnos$cgoldstandard?
Outcome
Howlikelyisthetesttopredict/ruleoutthiscondi$on?
Studydesign
Whatstudydesignwouldprovidethebestlevelofevidenceforthis
ques$on?
5
Pickingaresearchques$on
I.An$cipatetheResultsbeforeDoingFirstStudy
II.PickanAreaonBasisofInterestofOutcome
III.LookforanUnderoccupiedNicheHasPoten$al
IV.GotoTalks&ReadPapersoutsideAreaofInterest
V.BuildonaTheme
NEJM1994
6
Pickingaresearchques$on
VI.FindaBalancebtwLow-Risk&High-Risk
VII.BePreparedtoPursuetoAnyDepth
VIII.Dieren$ateYourselffromYourMentor
IX.DonotAssumeClinicalResearchIsEasier
X.Focus,Focus,Focus
NEJM1994
7
Outstandingproposal
NIHCri$queFINER
Feasibility
Interes$ng
Novel
Ethical
Relevant
8
Outstandingproposal
Feasibility
Technicalexper$setodowhatproposingtodo.
Pa$entrecruitment
demonstratethatyouhaveenoughpa$ents.
Manageableinscope.
Reasonable$meandmoney.
Interes$ng
Towhom?
Shouldbefascina$ngtoothers.
9
Outstandingproposal
Novel
Notalwaysmeanabsolutelynew&undonebefore.
Notrepea$ngsomethingalreadyknown.
Canuseknownmethods.
Eveniftwoprevioustrialsshowedconic$ngresults
toresolvetheresults
Goesfartherthanapreviousstudy
extentwhatwasshownbefore
Newapproach,newtechnique,newparadigm
(e.g.genomics,proteomics)
oienawardedonnoveltythanfeasibility/likelihood
10
Outstandingproposal
Ethical
Relevant
Scien$cclinicaloutcome
Ifthislackinknowledgeimportanttotheeld?
Clinicaloutcomesorclinicaldeliveryoutcomes?
Furtheringimportantnewdiscoveriesintheeld?
11
Outline
Deningresearchques$ons
Searchingliterature
Causalinference
Studydesigninclinicalresearch
Measurement
Databasemanagement
Somebiosta$s$cs
12
Howdoyousearch?
Whynotjustlookinatextbook?
Whynotjustreadafewpapers?
Doesdoingagoodsearchmaler?
Whatdatabasesareavailable?
Howdoesonesearch?
Noteasy!Dontunderes$mate
Obstacle:Notfoundorpublished.
13
Wheredoyousearch?
Primary,secondaryvs.Publicdatabase
PubMED/MEDLINEdatabase
CochraneCentralRegisterofControlledTrials
Othermedicalandhealthcaredatabases
EMBASE,ScienceCita$onIndex,,CINAHL,Psychlit
Non-Englishlanguageliterature
14
Wheredoyousearch?
Greyliterature
(theses,industryles,internalreports)
Referencesofprimarysources
(andreferencesofreferences)
Otherunpublishedsourcesknowntoexperts
(seekbypersonalcommunica$on)
Rawdatafrompublishedstudies
(seekbypersonalcommunica$on)
15
Outline
Deningresearchques$ons
Searchingliterature
Causalinference
Studydesigninclinicalresearch
Measurement
Databasemanagement
Somebiosta$s$cs
16
HillsCriteriaforcausa$on
Temporalrela$onship:anabsoluteone
Strength
Dose-responserela$onship
Consistency
Plausibility
Considera$onofalternateexplana$ons
Experiment
Specicity:weakestone
Coherence
17
Causaldiagram
18
Causaldiagram
19
Viral Load
Severity
Vaccination
Antiviral
+
S&S
BCP
Time since onset
+
Demographics
Causaldiagram
20
ThreattoCausalinference
Lackofprecision
Lackofinternalvalidity(accuracy)
Confoundingbias
Selec$onbias
Informa$on,measurementbias
Misclassica$onbias
Lackofexternalvalidity(generalizability)
Incorrectassessmentofdirec$onofcausality
21
Illustra$onofPrecisionvs.Accuracy
22
http://www.yorku.ca/psycho/en/postscript.asp
Illustra$onofPrecisionvs.Accuracy
23
http://upload.wikimedia.org/wikipedia/commons/3/38/Accuracy_and_precision.svg

SimpsonsParadox
24
25
26
Causaldiagram(again)
27
Selec$onbiasincohort
28
Selec$onbiasincohort
29
Berksons(Selec$on)biasincasecontrol
30
Diagnos$c(Selec$on)biasincasecontrol
31
Outline
Deningresearchques$ons
Searchingliterature
Causalinference
Studydesigninclinicalresearch
Measurement
Databasemanagement
Somebiosta$s$cs
32
EBMPyramid
33
Lancet 2002; 359: 57-61
34
35
Typeofclinicalstudies
Epidemiologicalstudy
Clinicaltrials
Evalua$onofdiagnos$ctestsandscreening
Systema$creviews/meta-analysis
Predic$on/prognos$csmodels
Compara$veeec$veresearch/Decision
analysis
Epidemiologicalstudy
Cross-sec$onalstudies
Case-controlstudies
Cohortstudies
Nestedstudies
Gene$cepidemiologicalstudies
Molecularepidemiologicalstudies
36
Studydesign:Cohortstudy
37
Epidemiologic Methods 752
1
November 20, 2006
Lecture 8
Lecture 8
Nested case-control and
case-cohort designs
2
Lecture objectives
Describe design features of nested case-
control and case-cohort studies
Understand the impetus for nesting case-
control and case-cohort studies in cohort
studies
Describe sampling schemes for each design
Contrast timing of exposure assessments in
nested case-control and case-cohort studies
3
Cohort study
3 events or cases occur
among 8 people, of
whom 5 are ever
exposed
Exposed are solid
lines, unexposed are
dashed
Dots are events
Time
P
e
r
s
o
n
s
4
Limitations of cohort study
Breadth of the study may limit measuring
exposure on everyone
Often number who develop outcome <<
number at risk

Optimize resources
5
Nested studies in a cohort - objective
Use a subsample of the cohort who have not
developed the disease without compromising
Highly useful when repository exists that may
be utilized to examine antecedent biomarkers
and too much precision validity
6
Cohort study
3 events or cases occur
among 8 people, of
whom 5 are ever
exposed
Exposed are solid
lines, unexposed are
dashed
Dots are events
Time
P
e
r
s
o
n
s
Studydesign:Nestedcase-control
38
Epidemiologic Methods 752
2
November 20, 2006
Lecture 8
7
Nested case-control study
Compare 3 cases to
3 non-cases (at time of
event)
Examples:
Lung cancer:
JAMA 1950;143:329-36
AIDS:
Ann Intern Med 1983;99:145-51
Time
P
e
r
s
o
n
s
(Incidence Density Sampling)
8
Case cohort study
Compare 3 cases to
non-case person-time in
random subcohort
Discard non-event
person-time outside
subcohort
Examples:
HCV:
Hepatology 2003;38:50-6
Time
P
e
r
s
o
n
s
S
u
b
c
o
h
o
r
t
9
Basic Idea for the Sampling
At each time at which one or more events are
observed in the cohort:
Compare those who developed the event to
subsets who were at risk at that time.
Typically,
the number developing event << number at risk
L So
a subsample of those at risk is sufficient.
Which subsample?
At attained time: nested case-control
At the beginning: case-cohort
10
Sampling Scheme for the
Nested Case-Control Design
11
Full Cohort
Events: A 1 1 2
S1 S6 S3,S8
At risk:
N 8 6 4
S1,S2,S3,S4,S5,S6,S7,S8 S3,S4,S5,S6,S7,S8 S3,S4,S7,S8
10
20 30 35
S1
S2
S3
S4
S5
S6
S7
S8
12
Defining the risk set
Who is at risk?
1) Cohort members
2) Same opportunity for observing the event
Using the same outcome time scale, had to been
followed for the same time
3) Cannot have a prior event
Sometimes potential confounders are added to
definition of risk set to balance comparative groups
on the external determinant - caution
Goal - Identify all members of the cohort at risk
for the event at the time the case is diagnosed
Studydesign:Nestedcase-cohort
39
Epidemiologic Methods 752
2
November 20, 2006
Lecture 8
7
Nested case-control study
Compare 3 cases to
3 non-cases (at time of
event)
Examples:
Lung cancer:
JAMA 1950;143:329-36
AIDS:
Ann Intern Med 1983;99:145-51
Time
P
e
r
s
o
n
s
(Incidence Density Sampling)
8
Case cohort study
Compare 3 cases to
non-case person-time in
random subcohort
Discard non-event
person-time outside
subcohort
Examples:
HCV:
Hepatology 2003;38:50-6
Time
P
e
r
s
o
n
s
S
u
b
c
o
h
o
r
t
9
Basic Idea for the Sampling
At each time at which one or more events are
observed in the cohort:
Compare those who developed the event to
subsets who were at risk at that time.
Typically,
the number developing event << number at risk
L So
a subsample of those at risk is sufficient.
Which subsample?
At attained time: nested case-control
At the beginning: case-cohort
10
Sampling Scheme for the
Nested Case-Control Design
11
Full Cohort
Events: A 1 1 2
S1 S6 S3,S8
At risk:
N 8 6 4
S1,S2,S3,S4,S5,S6,S7,S8 S3,S4,S5,S6,S7,S8 S3,S4,S7,S8
10
20 30 35
S1
S2
S3
S4
S5
S6
S7
S8
12
Defining the risk set
Who is at risk?
1) Cohort members
2) Same opportunity for observing the event
Using the same outcome time scale, had to been
followed for the same time
3) Cannot have a prior event
Sometimes potential confounders are added to
definition of risk set to balance comparative groups
on the external determinant - caution
Goal - Identify all members of the cohort at risk
for the event at the time the case is diagnosed
Cohortstudyvs.Case-controlstudy
Cohort Case-control
Prospec$veorretrospec$ve Retrospec$ve
Moreexpensive Ecient
Evaluatemul$pleoutcome Evaluatesingleoutcome
Repeatedmeasurement Onlyonemeasurement
Needlongtermfollowup Pronetoselec$onbias,
ascertainmentbias,diagnos$c
surveillancebias
40
Cohortstudyvs.Surveystudy
CohortStudy Survey/cross-sec;onalStudy
Purpose Causalinference Survey
Example NHANES NHAMCS
Sampling Convenient Systema$c
Generalizability Narrow Broad
Power/samplesize Common Dependonsamplingmethod
Feasibility/diculty
Cohort
retainment
Nonresponsebias/sampling
error
41
Clinicaltrials-phase
42
Conven;onal Descrip;ve
0 Transla$onal
I
Treatmentmechanism
I Dose-nding I
Dose-ranging
IIa Safety&ac$vity
IIb-III Compara$ve
IV Post-marking(expandedsafety)
Clinicaltrials-phase
43
44
Clinicaltrials-phase
Clinicaltrials-structure
45
CONSORT (Consolidated Standards of Reporting Trials)
Clinicaltrials-structure
46
Clinicaltrials-structure
47
Clinicaltrials-structure
48
Clinicaltrials-type
Randomized
Openlabel
Blinded/masked:single,double,triple
Placebo/comparatercontrolled
Non-inferiority/equivalent
Factorial:interac$on
Cross-over:comparetooneself
49
Evalua$onofdiagnos$ctestsandscreening
Bias:verica$on,spectrum
Goldstandardissue
Discrimina$onvs.Calibra$on
ROC,goodness-of-t
Performanceissue
Sensi$vity,specicityvs.PPV,NPV
Likelihoodra$o,thresholdmodel
50
9/25/12 Kuan-FuChenCGMHEM
Epidemiology2x2nightmare
Diseased Healthy
Test(+) A C
Test(-) B D
Performance Detail
Sensi$vity
Specicity
PPV
NPV
LR(+)
LR(-)
51
9/25/12 Kuan-FuChenCGMHEM
Epidemiology2x2table
Diseased Healthy
Test(+) A C
Test(-) B D
Performance Detail
Sensi$vity A/A+B
Specicity D/C+D
Posi$vePredic$veValue A/A+C
Nega$vePredic$veValue D/B+D
Posi$veLikelihoodra$o Sensi$vity/(1-Specicity)
Nega$veLikelihoodra$o (1-Sensi$vity)/Specicity
52
9/25/12 Kuan-FuChenCGMHEM
Prevalentperiod
Diseased Healthy
Test(+)
A
C
Test(-)
B
D
Performance Detail
Sensi$vity
A/A+B
Specicity D/C+D
Posi$vePredic$veValue
A/A+C~100%
Nega$vePredic$veValue
D/B+D~0%
53
9/25/12 Kuan-FuChenCGMHEM
Non-Prevalentperiod
Diseased Healthy
Test(+)
A
C
Test(-)
B
D
Performance Detail
Sensi$vity A/A+B
Specicity
D/C+D
Posi$vePredic$veValue
A/A+C~0%
Nega$vePredic$veValue
D/B+D~100%
54
Outline
Deningresearchques$ons
Searchingliterature
Causalinference
Studydesigninclinicalresearch
Measurement
Databasemanagement
Somebiosta$s$cs
55
Measurement
Ques$onnaire
Developmentandvalida$on
Retrospec$vedatabase
HIS+SAS+SQLinCGMH>NHIRD
Specimens&Assay:valida$on
Informa$onbias:recallbias
Followup:censoringissue(missingness)
56
Outline
Deningresearchques$ons
Searchingliterature
Causalinference
Studydesigninclinicalresearch
Measurement
Databasemanagement
Somebiosta$s$cs
57
MicrosoiAccessasthetool
58
MicrosoiAccessasthetool
59
MicrosoiAccessasthetool
60
MicrosoiAccessasthetool
61
Outline
Deningresearchques$ons
Searchingliterature
Causalinference
Studydesigninclinicalresearch
Measurement
Databasemanagement
Somebiosta$s$cs
62
Sta$s$calinference
63
64
h"p://www.intuitor.com/sta2s2cs//CentralLim.html7
65
Samplesizecalcula$on
Freesoiware
PS:PowerandSampleSizeCalcula$onhttp://biostat.mc.vanderbilt.edu/
twiki/bin/view/Main/PowerSampleSize
G*Powerhttp://www.psycho.uni-duesseldorf.de/abteilungen/aap/gpower3/
UiowaJAVAhttp://www.cs.uiowa.edu/~rlenth/Power/
Freewebsite
OpenEpihttp://www.sph.emory.edu/~cdckms/sample%20size%202%20grps%20cohort.htm
Raosoiforsurveystudyhttp://www.raosoft.com/samplesize.html
UBCCAhttp://stat.ubc.ca/~rollin/stats/ssize/b2.html
Samplesizecalcula$on
66
Samplesizecalcula$on
67
68
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Ques$ons?
kfchen@cgmh.org.tw
69