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Evidence Based Medicine
Blok 3 FK Muhamadiyah
Oleh
Prof.DR.Dr.R.M. Suryadi Tjekyan DTM&H.MPH
EPIDEMILOGI
KLINIK
SEBAGAI
METODA
Pengobatan
CRITICAL
APPRAISAL
Pencegahan
Kausa
Perjalanan/Riwayat
alami
Give T=the
Best to The
Patients
area penelitian
biologic onset
(patobiology)
Risk factors
(Causation)
early diagnosis
possible
usual clinical
diagnosis
Dx
End Points
sembuh
komplikasi
cacad
mati
Prognostic
Diagnostic
Factors
test
Clinical Trials
Diagnostic
Therapy
Clinical Trials
test
Clinical Trials
Prevention I
Prevention II
Screening
EPIDEMIOLOGI KLINIS
Batasan epidemiologi klinis adalah studi
mengenai variasi luaran (out come) dan
perjalanan dari penyakit pada perorangan atau
Best to The
Patients
Objectives
1. Memahami dasar dasar Evidence Based Mediccine
2. Memahami Health Service Research(Penelitian
Pelayanan Kesehatan) sebagai
bagian dari
Epidemiologi
3. Memahami batasan penyakit , sakit dan resiko
yang ditimbulkannya.
4. Memahami keadaan Normal dan Abnormalitas
5. Memahami Aplikasi klinis dari RR , RD dan
NNT(Risk Ratio,Risk Difference dan Number
Needed to treat)
APA PERANAN
EPIDEMIOLOGI KLINIK
keilmuan dasar
metode
dan Abnormalitas
Diagnosis
Kekerapan/Frekuensi
Risiko
Prognosis
Pengobatan/Terapi
Pencegahan
Kausa
Perjalanan/Riwayat
alami
Last (1995):
a)
Normal
KOLESTER
Kolesterol
darah
10
0
100.0
120.0
110.0
140.0
130.0
160.0
150.0
180.0
170.0
200.0
190.0
220.0
210.0
240.0
230.0
KOLESTER
2.
3.
EBM
Started in early 90s by clinical
epidemiologists
1992
: only few articles on EBM
2000
: >1000 articles
Indonesia
: started in 1997
Workshops : Yogya (2000)
IKA FKUI (2000, 2001)
Group discussion on EBM / mailing list:
<ebm-f2000@yahoogroups.com>
(coord:
<firmanda@cabi.net.id>)
1360
1370
1200
965
1000
86
5
800
599
600
400
213
200
2
1964 -1991
2001
1993
1
0
7
5
1995
1997
1999
Science
Deductive learning
Every Friday
Dr. AT is on call
Today is Friday
Therefore
Dr. AT is on call
Inductive learning
Resident A is neat
Resident B is neat
Resident C is neat
etc
Therefore:
All residents are neat
Previous practice:
6 yrs medical
education
40-50 yrs
medical practice
Consultant, colleagues
Textbooks
Handbooks
Lecture notes
Clinical guidelines
CME, seminars, etc
Journals
What is Evidence-based
Medicine?
The conscientious, explicit, and judicious use
of current best evidence in making decisions
about the care of individual patients
Integration of
studies, and
preference
Pros
WHY EBM?
1.New evidence are continuously
generated
2. We usually fail to get the new evidence
3. Our clinical performance deteriorates
with
time (the slippery slope)
4. Traditional CME does not improve
clinical
performance
5.EBM encourages self directed learning
process which should overcome the
above shortages
100%
Relative
% of
remaining
knowledge
10
12
Main area
Diagnosis
(Determination of disease or problem)
Treatment
(Intervention necessary to help the patient)
Prognosis
(Prediction of the outcome of the disease)
Others:
Meta-analysis
Clinical guidelines
Economic analysis
Clinical decision making
Cost-effectiveness analysis
Qualitative research
(I)
Formulating clinical questions
Medical students:
(Background question)
What is VSD?
How to Dx?
What are symptoms & signs of
CHF
in infants with L-R
shunt?
What is the treatment?
House officers
(Foreground question)
Other example
Four elements of
good clinical question: PICO
The Patient or Problem
The Intervention
Comparative intervention (if
relevant)
The Outcome
Harm
A 15-month-old infant was brought for MMR
vaccination. The mother inform that her daughter is
very allergic to egg. Knowing that all MMR vaccine
contain small amount of egg protein ovalbumin,
Question formulation:
P:
I:
O:
II
Searching the evidence
http://bmj.com
http://adc/bmjjournals.co
m
MEDLINE/PubMed
EMBASE
MDConsult
AAP Journal Club
Cochrane Library
III
Appraising the evidence:
VIA
VIA
VALIDITY: In Methods section:
Example:
Critical appraisal for therapy
Were the subjects randomized?
Were all subjects received similar treatment?
Were all relevant outcomes considered?
Were all subjects randomized included in the
analysis?
Calculate CER, EER, RRR, ARR, and NNT
Were study subjects similar to our patients in terms
of prognostic factors?
Hierarchy/Level of evidence
I
a. Meta-analysis of RCT
b. Large RCT
II a. Controlled trial without randomization
b. Cohort, case control studies
III a. Cross-sectional
b. Case series, case reports
IV
Expert opinion
Clinical guidelines
Practice development leaders
(! Environment)
Development units
Dissemination of good
practice
Networking
Research summaries
Action research
Physicians proficiency
Evidence
Patients preference
Patient with
problem
Apply
the evidence
Critically
appraise
the evidence
Formulate
in answerable
question
Search the
evidence
Sources of
evidence
Good clinical
question
Recent relevant
literature
Problem
identification
Valid, important,
applicable
evidence
Patient
Integration of
current evidence
into practice
Advantages of EBM
Encourages reading habit
Improves methodological skill (and
willingness to do research?!)
Encourages rational & up to date
management of patients
Reduces intuition & judgment in clinical
practice, but not eliminates them
Consistent with ethical and medico-legal
aspects of patient management
End result
self directed, life-long learning attitude
for high quality medical management
Conclusion
EBM is nothing more than a
framework of systematic use of
current valid study results
relevant to our patient
Remember, however
...
Medicine is the science of uncertainty
and the art of probabilities
P
I
C
O
: Patient or Problem
: Intervention
: Comparative intervention
: Outcome
How would I
describe a
group of
patients
like mine?
B e
Which main
intervention
am I
considering?
b r i e f
What is the
What can I
alternative
hope
to compare
from this
with the
intervention?
intervention?
a n d s p e c i f i c
Example 1:
Etiology
P
O
lead to
increased
likelihood of
heart failure?
Differential diagnosis
P
In SLE
.with pre- .and taking .which one
patients
existing
and taking Is more likely
with new
Cardiac
NSAID
explanation?
onset
Involvement
heart failure
Prognosis
P
In young
female
SLE
does
devment of
heart failure
.compared lead to
with no heart increased
mortality?
failure
Therapy
P
In SLE
patient on
ibuprofen
with
heart
failure
I
would
removal of
NSAID
and
addition
of diuretic
C
versus
NSAID
removal plus
diuretic plus
ACE inhibitor
O
alleviate
heart
failure?
Prevention
P
In SLE
patients
with
heart failure
I
.would
long-term
ACE
Inhibitor
C
compared
with no
ACE
inhibitor
O
prevent
recurrence
& improve
quality
of life
Example (2)
Female, 73 years, shortness of breath on
Etiology
P
In elderly
female with
CHD
O
lead to
increased
likelihood of
heart failure?
Differential diagnosis
P
Example: Prognosis
In elderly
does
.compared lead to
female
development with no heart increased
patients of heart failure
mortality?
failure
with CHD
Example: Therapy
P
In CHD on
ibuprofen
with
heart
failure
I
would
removal of
NSAID
and
addition
of diuretic
C
versus
NSAID
removal of
diuretic plus
ACE inhibitor
O
alleviate
heart
failure?
Prevention
P
In patients
with
heart failure
I
.would
long-term
ACE
Inhibitor
C
compared
with no
ACE
inhibitor
O
prevent
recurrence
& Improve
quality
of life
(again)
previously responsive to antacids
you suspect H. pylori and suggest referring for
endoscopy
after describing what is involved, patient is not
keen and asks if there is another test
you agree to find out about sensitivity and
specificity of non-invasive tests
Diagnosis
P
in patients
(men?) with
recurrent
stomach
complaints
responsive to
antacids
is noncompared
invasive
with
diagnostic test endoscopy
(breath test)
O
as sensitive
and specific at
identifying H.
pylori status
Problem 2 - Prevention
male, 28 years, with symptoms
suggestive of influenza
illness has caused misery, resulted in
time off work (self-employed)
aware that elderly are vaccinated, wants
to know if it can benefit him next year
you decide to look for evidence on
efficacy of vaccine among young, healthy
adults
Prevention
P
In healthy
adults
is influenza
immunization
compared effective in
with no
reducing
immunization
incidence
of flu
Problem 3 - Therapy
Infant, 13 months, experienced 2
attacks of febrile convulsions
Variable recommendations on the use of
maintenance anticonvulsants
Not sure whether to give or not in order to
prevent further attacks
Therapy
P
In infants
with
repeat
febrile con
vulsion ..
I
.. is anticonvulsant
drugs
compared
with
no drugs
better
control
further
seizure
Problem 4 - Prognosis
Female, 46 years, had ulcerative colitis for 11
Prognosis
P
In middleaged
women
with history
of ulcerative
colitis
cf no
colitis
what is
the risk of
developing
Ca
Concluding remark
In patient with
X and X, would the
administration of
Y or Y, decrease the
likelihood of
developing
so and so?
HYPOTHESIS TESTING
&
ESTIMATION
(P value & Confidence Interval)
P
S
P
S
Target population
Accessible
population
Intended
Sample
Actual
study subjects
Target population
(Demographic & clinical)
Accessible
population
(+ time, place)
Appropriate
sampling
technique
Actual
study
subjects
Subjects
completed
the study
Intended
Sample
[Subjects selected
for study]
Target population
Accessible
population
[External validity I:
Does IS represent AP?}
Actual
study
subjects
Intended
Sample
Sampling
Investigation
Results
Inference
P value
Confidence intervals!!!
220
Standard, n= 5000
Clinical
Experimental, n=5000
300
t=
df = 9998
218
p = 0.0023
Statistical
No
Standard
10
New
Clinical
Statistical
Examples of statistics:
Proportion
Percentage
Mean
Median
Mode
Difference in
proportion/mean
OR
RR
Sensitivity
Specificity
Kappa
LR
NNT
P value
Confidence Interval
How to calculate CI
General Formula:
CI = p Z x SE
Example 1
100 FK-Unsri students 60 females (p=0.6)
What is the proportion of females in Indonesian
FK students? (assuming FKUnsri represents FK
in Indonesia)
Example 1
SE(p)CI pq
n
95%CI 0.61.96 0.6x0.4
100
0.61.96x0.5
10
0.6 0.1 0.5;0.7
SE(p1 p 2 )
p1q1 p1q2
n2
n2
0.09
50
50
50
95%CI(p1 p 2 ) (0.2 0.9); (0.2 0.09) 0.11; 0.29
1
1
SE(x 1 x 2 ) 17.7
3.53
50 50
95%CI 6.0 (1.96X3.53) 1.0;13.0
Relative risk
Odds ratio
Sensitivity, specificity
Likelihood ratio
Relative risk reduction
Number needed to treat
(RR)
(OR)
(Se, Sp)
(LR)
(RRR)
(NNT)
Examples
RR
OR
NNT
= 5.6
= 12.8
= 12
Concluding remarks
Concluding remarks
Concluding remarks
Diagnosis
Nilai Uji Diagnostik tergantung dari
Keterandalan (reliability),
Kesahihannya (validity)
Relevansinya
1. Sensitivitas/Sensitivity
2. Spesifisitas
3. Nilai Prediksi Positif
4. Nilai Prediksi Negatif
4. Likelihood ratio +
5. Likelihood ratio
( Likelihood ratio = Ratio kemungkinan )
Likelihood Ratio
= a/ a+b
= b/b+d
= c/a+c
= d/b+d
Prevalen = (a+c)/(a+b+c+d)
Tes
Penyaringan
Penyakit
Total
+
a
(positif asli)
Total
(positif palsu)
a+b
(total tes positif)
(negatif palsu)
d
(negatif asli)
c+d
(total tes negatif)
a+c
(total
penyakit)
b+d
(total bukan
penyakit)
a+b+c+d
(total keseluruhan)
Sensitivitas = ( a / ( a + c )
Spesifisitas = (d/ ( b + d )
Akurasi
= (a+d)/(a+b+c+d )
Infark miokard
Kreatinin kinase
Total
Ya
Tidak
215
16
231
15
114
129
Total
230
130
360
Sensitivitas
Spesifisitas
=
=
NPP
NPN
215/231 x 100
114/129 x 100
=
=
215/230 x 100
114/130 x 100
= 93,5%
= 87,7%
= 93,1 %
= 88,4 %
Infark miokard
Likelihood
Rasio
Kreatinin kinase
Ya
Proporsi
Positif > 80 IU
215
215/231 = 0,9348
Negatif < 80 IU
15
15/231 = 0,0652
Total
230
Tidak Proporsi
16 (16/130 = 0,1231)
0,9348/0,1231 = 7,5938
0.0652/0,8769 = 0,0743
130
360
Nilai likelihood ratio dari skrining adalah sama dengan odd ratio.
Hanya kasus
yang memerlukan tes diagnostik
PJK
+8%
+
tredmil
prob. pascates
540
549
360
91
451
900
probab (prates) PJK
(pascates)
100
540
----- =
549
1000
90%
98%
98%
probabilitas
menderita PJK
dari 90% ke
98%, tidak
perlu tredmil
lab: normal
probabilitas (prates ) PJK 50 %
PJK
(angiografi koroner)
tredmil
prob. pascates
+
+
300
45
345
200
455
655
500
950
87%
+37%
1000
50%
300
----- =
345
87%
probabilitas
menderita PJK dari
50% ke 87 %,
Perlu tredmil
General structure :
2 X 2 table
Predictor
Test
positive
Predictor
Test
negative
Target disorder
Positive
(disease)
True positive
TP
a
False negative
FN
c
Target disorder
Negative
(normal)
False positive
FP
b
True negative
TN
d
Critical appraisal
Use worksheet
Use supporting softwares
CAT
Maker
Save in CAT Banks
validity
SnNOut
SpPIn
Disease
(+)
Disease
(-)
Totals
Test (+)
a+b
Test (-)
c+d
b+d
a+b
+c+d
d/b+d
Specificity
Totals
Sensitivity
a+c
a/a+c
SnNout
Diagnostic test with a very high sensitivity ,
a negative result effectively rules out the
diagnosis
SpPin
Diagnostic test with a very high specificity ,
a positive result effectively rules in the
diagnosis
Disease
(+)
Disease
(-)
Totals
a+b
c+d
a+c
b+d
a+b
+c+d
Totals
Sensitivity=a/a+c=90%
Specificity =d/b+d=85%
Pos predictive value=a/a+b=73%
Neg predictive value=d/c+d=95%
Outcome
Totals
Present
Absent
(+)
<65 mmol/L
731
a
270
b
1001
a+b
(-)
>65 mmol/L
78
c
1500
d
1578
c+d
1770
b+d
2579
a+b+
c+d
Predictor
Diag
nostic
test
result
(Serum
ferritin)
LR + = se/(1-sp)=90/15=6
Totals
809
a+c
(1-Se)/Sp= -
+ = Se/(1-Sp)
Likelihood ratio
do not
test
do not
test
Test
do not
treat
.10
Test
.20
.30
.40
.50
.60
.70
.80
pretest probability
posttest probability
PreTest odds x LR
pretest probability
.90
Pretest
probability
Likelihood ratio
Posttest
probability
0.90-1.00
0.80-0.90
0.70-0.80
0.60-0.70
0.50-0.60
=
=
=
=
=
excellent (A)
good (B)
fair (C)
poor (D)
fail (F)
2.
3.
4.
Effect
Death
Outcome
Cost
Disease
Risk difference= IE - IC
Contoh
Intervensi : Fosamax; Controls: Placebo
Outcome: Fraktur Klinis
IE = 11.9 per 100; IC = 14.7 per 100
Risk difference = 11.9-14.7 = -2.8 per
100
RR = IE/IC
(incidence
in exposed) / (incidence in
non-exposed)
Contoh:
Intervensi: Fosamax; Controls: Placebo
Outcome: Fraktur Klinis
IE = 11.9 per 100; IC = 14.7 per 100
RR = 11.9/14.7 = 0.81
RR = 1
RR > 1
RR < 1
No
Total
Yes
a+b
No
c+d
Exposure
Yes
No
40
360
400
200
1400
1600
Regular
Exercise
No
RR
= I(e)
I(ne)
Interpretation:
a/(a+b)
c/(c+d)
Hip Fracture
(cases)
Received
Health
Promo
a
Did Not
Receive
Health
Promo
c
No
Hip Fracture
(controls)
Received
Health
Promo
b
Did Not
Receive
Health
Promo
d
No Hip Fx
(controls)
Promo
No Promo
Total
a+c
b+d
ad
bc
No
Hip Fx
Promo
100
200
No Promo
900
800
Odds Ratio =
Interpretation:
Smokers
Non-Smokers
Total
Odds Ratio
Interpretation:
Cases
Controls
120
170
80
230
200
400
Adjusted Risk
Resiko yang disesuaikan
Kegunaan
Metoda Penyesuaian/Adjustment
Standarisasi
Mantel Haenszel
Log-linear models
risk models
odds models
rate models
incidence-time models
Jumlah
Latihan
Postif
Negatif
Positif
170
80
250
Negatif
80
170
250
250
250
500
Odd ratio
2.13
4.52
0.36
0.53
0.36
[1.74,
[3.10,
[0.28,
[0.43,
[0.27,
2.59]
6.58]
0.44]
0.61]
0.44]
1.
2.
3.
4.
5.
6.
Umur kelompok MI, 80% orang berusia diatas 50 tahun dan hanya 20 %
pada kelompok Non MI termasuk kelompok usia > 50 tahun tersebut .
Apakah perbedaan usia pada dua kelompok dapat menjelaskan hubungan ini
atau sepenuhnya resiko 4.52 kali tersebut hanya dipengaruhi oleh faktor
tidak olah raga/latihan dan tidak dipengaruhi oleh umur
Harus dibuktikan dulu bahwa umur bukan confounder
Bila umur adalah confounder maka dipertanyakan berapa sebenarnya resiko
terjadinya MI yang memang disebabkan oleh faktor tidak latihan/olahraga
sebaliknya
Umur bukan confounder maka berarti resiko terjadinya MI pada kelompok
yang tidak berolahraga memang 4.52 kali dibandingkan dengan yang
berolahraga atau dengan kata lain insiden MI pada kelompok berolahraga
dibandingkan tidak berolah raga adalah 1 : 4.52 dimana setiap 100 pasien MI
kelompok yang berolaharaga maka didalam populasi terdapat 452 kasus MI
kelompok individu yang tidak berolah raga.
Subjek studi menjadi dua kelompok yaitu usia
6.1. dibawah 50 tahun
6.2. lebih dari 50 tahun
6.3. Dilihat hubungan antara latihan dan kejadian MI pada masing-masing
kelompok usia.
1.
2.
CONFOUNDER POTENSIAL
Adjusted RR
Myocardial Infarction
Yes
No
Total
Education
High School
100
1700
1800
60
1140
1200
130
2570
2700
1-4 years
105
110
5-9 years
10
120
130
10 + years
15
45
60
160
2840
3000
College
Oral Contraception
Never
Total
Adjusted RR
Myocardial Infarction
Crude
Adjusted*
95% C.I.
RR
RR
Education
High School
1.11
--
--
--
--
--
1-4 years
0.98
1.0
(0.9-1.1)
5-9 years
1.60
1.3
(0.9-1.7)
10 + years
5.20
4.1
(2.1-6.1)
College
Oral Contraception
Never
Perlakuan: Fosamax
Controls: Placebo
Outcome: Fraktur Klinis
CER = 14.7 per 100; EER = 11.9 per 100
ARR = 14.7-11.9 = 2.8 per 100
TERAPI / PENGOBATAN
memilih terapi yang terbaik untuk penderita
Intervention
PICO
Comparison Intervention
SOFTWARE
TELAAH KRITIS
ARTIKEL/CRITICAL
APPRAISAL
Outcome
LIST OF ARTIKEL
1.1.
1.2.
1.3.
Telaah abstract:
Apakah hasil studi cocok dengan dengan kita butuhkan bila ya
lanjutkan bila tidak stop jangan dibaca.
Apakah permasalahan yang disajikan sering dijumpai pada praktek
anda sehari hari di RS dan intervensi yang dilakukan laik untuk
dilakukan bila ya lanjutkan bila tidak stop
Apakah informasi yang didapat dari artikel tersebut dapat
membawa perubahan pada cara perawatan pasien ditempat anda `
pada saat ini. Bila ya lanjutkan bila tidak stop
ACTIVE Rx
.22
0,8
.10
.04
Parameter
Relative Risk
Reduction (RRR)
Placebo
P
Active Rx
A
(P A) = RRR
P
.22
.08
.22 0.8= 64
.22
No prior target
.10
0.4
.10 0.4 = 60
.10
Parameter
Ukuran Resiko
Patients status at
entry
Placebo
P
Active Rx
A
RRR
Absolute Risk
Reduction
.22
.08
64%
.22 - .08 = 14
No prior organ
damage
.10
0.4
60%
1.
2.
KAUSA
ASOSIASI
ASOSIASI
SEMU
ASOSIASI
MURNI
1.STRATIFIKASI MANTENHAENZEL
2.LOGISTIK REGRESSION
OXIDATIF
LDL
KOLESTEROL
TINGGI
1.COVARIAT
2.CONFOUNDING
ASOSIASI
MURNI
M.C.I
1.UMUR
2.ROKOK
3.OVERWEIGHT
4.OLAHRAGA
5.GENETIK
6.STRESS
7.HIPERTENSI
8.PERILAKU MAKAN
ASOSIASI
SEMU
ASOSIASI SEMU
desain
Tentukan
Fase
analisis
Mengumpulkan
efek kausa
Fase desain
Fase analisis
PROGNOSIS
Prognosis
perjalanan
PERBEDAAN
RESIKO DAN PROGNOSIS
1. Resiko memprediksi kejadian-kejadian probabilitas
yang
rendah,
sedangkan
prognosis
menggambarkan kejadian yang relatif sering.
(KEJADIAN)
Timbul
Penyakit
Tanpa
Penyakit
resiko
Faktor
Resiko
Keluaran
penyakit
Prognosis
Faktor
Prognostis
Kematian
Kecacatan
Kekambuhan
dll
P.I.C.O
Critical appraisal
Applying evidence
- Respons
- Remisi
- Kekambuhan
yang
sesudah
Prevensi
: apakah dengan
intervensi penyakit dapat dicegah,
apakah deteksi dini dan
pengobatan dapat memperbaiki
perjalanan penyakit.
Kausa : kondisi apa yang
menimbulkan penyakit ? apa
mekanisme patogenetik