6

171

Les6-p 171-242.indd 171 4/27/11 5:23:01 PM



(Statistical Analysis Plan SAP)

(endpoints)
2
(primary endpoints)

(secondary endpoints)


(variance)
(primary objective)


/







(
)




/
( 1)
1. /
(Study endpoints)

172

Les6-p 171-242.indd 172 4/27/11 5:23:01 PM



1:

mortality
/


5 (quality of recurrence
life scale)

PANSS BPRS

/ ICH

guideline (E9)[1]

173

Les6-p 171-242.indd 173 4/27/11 5:23:03 PM



Do Tirofiban

and ReoPro Give Similar Efficacy Trial.
Comparison of two platelet glycoprotein

IIb/IIIa inhibitors, tirofiban and abciximab,
for the prevention of ischemic events
with percutaneous coronary revas-
cularization New England
(com- Journal of Medicine. Vol. 344 (2001)
posite variables) 2


(noninferiority trial)

3 events (death +

myocardial infarction + urgent target
vessel revascularization)
( + + ) 30 ( 1)[2]
2.
( + (Efficacy & safety variables)
+ )

(validity) (
(reliability) )

2 (effectiveness)

(safety)

174

Les6-p 171-242.indd 174 4/27/11 5:23:04 PM



1
( New England Journal of Medicine Massachusetts Medical
Society)

30 - day Death, MI, Urgent TVR

Noninferiority
R.R. = 1.26 Upper bound boundary
p = 0.038 of 95% C.I.
= 1.51 R.R. = 1.26
30 -day Death, MI, Urgent TVR (%)

10%

8% 7.6%
6.0% Abciximab
6% Better
4%

2% Tiroban
Better
0%
Tiroban Abciximab

Tiroban Abciximab
8% 7.6% 7.2%
6.9%
6.0% 5.7%
6% 5.4%
Event Rate

4%
p = 0.038 p = 0 .6 6 p = 0.04 p = 0.04 p = 0 .4 9
2%
0.5% 0.4% 0.8% 0.7%
0%
Composite Death MI Death/MI Urgent
TVR

175

Les6-p 171-242.indd 175 4/27/11 5:23:04 PM



1 (phase I) 2 (phase II)

3 (phase III)
3.


(independent
variable) /
3 (dependent variable)

(external/control variables)

[4,5]

(US-FDA)[1,3]

3.1 (Binary)





12



3



(propor-

176

Les6-p 171-242.indd 176 4/27/11 5:23:05 PM



tion) (rate) (risk)

(odds ratio) relative risk 3.5 (Continu-

( ) ous)

3.2 (Count)

CD4

30
(mean)

2

3.6 (Time to event)




(count per unit
time)



(incidence density ratios)
3.3 (Categorical)


2
3


2
3.4 (Ordinal)
( )


4 (censored)

177

Les6-p 171-242.indd 177 4/27/11 5:23:05 PM



(averaged relative risk)

(hazard risk ratios)
3.7

3
57 3
(likert scale)
(pain score)
10

3


4.




Generalized
Estimating Equation GEE

/
(randomeffects model) 2

(multiple

measurements)

[6,7,8,9]

178

Les6-p 171-242.indd 178 4/27/11 5:23:05 PM



17 9

VKC

1 A Randomized
(not eye specific)

Trial of Low-Dose, Topical Mitomycin-C

in the Treatment of Severe Vernal Kera-

(patient)

toconjunctivitis Ophthalmo-
VKC

logy, Vol. 107, (2000)[10]

VKC
(eye) ( 2)

26

(placebo) 2:1

2
( Ophthalmology American Academy of

Opthelmology)

179

Les6-p 171-242.indd 179 4/29/11 2:12:00 PM



ICSI Laser-
assisted ICSI
59
p < 0.01 (mature oocytes)
( p-value 6
775
)
2 No advan- ICSI (
tage of laser-assisted over conventional ) ICSI
intracytoplasmic sperm injection: a ran- Laser-assisted ( )
domized controlled trial Journal
of Experimental & Clinical Assisted
Reproduction (2006)[11] (oocytes)
2

Intracytoplas-
mic Sperm Injection ICSI ( 3)

3
Table I: Mean clinical outcomes per cycle compared betwee laser-assisted and conventional ICSI

of msyutr (MII) cocytes, including within-patient correlation coefficients (r).

( Open Access Journal of Experimental &

Clinical Assisted Reproduction)

180

Les6-p 171-242.indd 180 4/27/11 5:23:07 PM



3 A rand- intervention)

omized clinical trial comparing hydrocol-

loid, phenytoin and simple dressings for
the treatment of pressure ulcers
BMC Dermatology (2004)[12]

3 (practices) cluster
(sample dressing),

(phenytonin
cream)
(hydrocolloid dressing)
83
91


(baseline)
()
( 4) ()
4 Rational GEE
Prescribing in Primary Care (RaPP): A cluster effect

cluster randomized trial of a tailored

intervention PLoS Med ( )

(2006)[13] ( 5)

(passive guideline dissemination)

(tailored
181

Les6-p 171-242.indd 181 4/27/11 5:23:07 PM



4

( Open Access BMC
Dermatology)

182

Les6-p 171-242.indd 182 4/27/11 5:23:23 PM



5

( Open Access PLoS Medicine)

a
b
Adjusted for baseline differences clustering effects (GEE).
Fewer data on exclusion criteria were available for the baseline period, explaining the higher number of prescription than during follow-
up.
c
Recommended treatment goal for blood pressure is less than 140/90 mm Hg; for lipids is total cholesterol < 5 mmol/l (190 mg/dl) and/or
LDL cholesterol < 3 mmol/l (115 mg/dl).
DOI: 10.1371/journal.pmed.0030134.t002

183

Les6-p 171-242.indd 183 4/27/11 5:23:26 PM



H0
2
(standard treatment)
( 5 100 )

(research hypothesis)

(statistical H0
hypothesis) (not reject) H0



1.

(significance testing)

(onetailed
onesided)
Null (twotailed twosided)
Hypothesis H0
2 (hypothesis formulation)

()

(probability)
(acceptance) H 0
95 (pro-
(rejection) H0 5 bability estimate) H0

184

Les6-p 171-242.indd 184 4/27/11 5:23:26 PM



H0
H 0
( p-value = 0.05) [4,14]



2


H0 (null hypothesis) H0 : 1 2
Ha (alternative hypothesis) H0 : 1 2

H0 (null hypothesis) H0 : 1 2
Ha (alternative hypothesis) H0 : 1 2

H0 (null hypothesis) H0 : 1 2
Ha (alternative hypothesis) H0 : 1 2

(predetermined direc- ()
tion)

185

Les6-p 171-242.indd 185 4/27/11 5:23:27 PM



[15,16,17]
p-value=0.05
(post-marketing surveillance)
X X
(relative risk) ( Z statistics) p=0.05
Y +1.64 -1.64
X
+1.96
-1.96
1.85
H0

X
Y H 0 ( 1.85>1.64)

H0 (
1.85<1.96)( 6)

H0

(a priori)

186

Les6-p 171-242.indd 186 4/27/11 5:23:29 PM



2



H 0
(Significance level)
significant
(conservative) [16,17] impor-
tant ()

significant


(probably
true, not due to chance)
(equality) (superiority)
(non-inferiority) highly significant
(equivalence) 4


( 4)



(statistical significance)

(clinical public
[18,19] health importance)

2.






Intelligence Quotient IQ
1,000
187

Les6-p 171-242.indd 187 4/27/11 5:23:29 PM



IQ
(= 100) IQ
(= 98)
0.001
(so what?) p-value (probability
2 value) p-value

?



25

p-value


[20,21]
(inferential
statistics)
( ) 5
2 5


(population) 95

(sample) p

p=0.027
(p<0.05) (p>0.05)

p-value 3
188

Les6-p 171-242.indd 188 4/27/11 5:23:29 PM



p=0.003

1 2 p=0.1 p=0.39
p
p<0.001 p<0.0001
[22]
(Confidence
level)

(Confidence Interval CI)
2
2

(plausibility) (estimate)
2
(inference)
p value
point estimate
95
2 ( ( 95CI)
)

2
2 interval estimate
95CI

95CI

95

2 2
Roald Koffman
Nobel Prize .. 1981

189

Les6-p 171-242.indd 189 4/27/11 5:23:29 PM



2
95CI
2 X (t 0.05,9 x SD
1 n) 6.3 1.94
2 0 95CI /

95CI 4.36 8.24 48

( 10
20 = 20 x 10 ) 6.0

95CI 95CI 48

95 6 48

20 95CI

100 95

95CI (6 ) 19 ( 95

[4,23] 20 )

1 ( 5 20 )

20 95CI

( 3 7)
95CI

20 10

1
p-value
10
95CI
6.3 6 /

2.71
95




190

Les6-p 171-242.indd 190 4/27/11 5:23:30 PM



7 95CI

1
95CI
[16,18,24] / (compliance/adherence)

/
(Analysis data sets) (violation/deviation)




(longitudinal study)

1, 3, 6
4

3

191

Les6-p 171-242.indd 191 4/27/11 5:23:44 PM



(IntentionToTreat

ITT)

ITT
(
ICH Guideline E3)[25]


ITT
(1)
,

(2)
1 (Type I error)
( Type I error
)

1.
(inclusion criteria eligibility
violation)

(

ITT

192

Les6-p 171-242.indd 192 4/27/11 5:23:45 PM



- / (Last Observation Carried

Forward LOCF)

- -

( GEE)

( / /)

)
- - 2.



(valid cases)
ITT (effectiveness
sample)
(evaluable samples)



-

(imputation technique) (

193

Les6-p 171-242.indd 193 4/27/11 5:23:45 PM



3. Intention-

) To-Treat Pre-Protocol
-

- / (sensitive)

(confirmatory trial)
Per-Protocol PP


( ITT PP)
PP

2
ITT PP

2
(

)
ITT
PP



PP
PP
(validity)
PP
ITT PP

PP
(

PP

194

Les6-p 171-242.indd 194 4/27/11 5:23:45 PM



superiority trial) 1 What is meant

( by intention to treat analysis? Survey of
published randomised controlled trials
, equivalence/ British Medical Journal,
non-inferiority trial) Vol.319 (1999) [26]


ITT

ITT PP
ITT (
as-treated
[ 15,

17,18]

( 8)

8
( British Medical Journal British Medical
Journal Group, Ltd)

195

Les6-p 171-242.indd 195 4/27/11 5:23:46 PM



2 A phase
PP According

2b randomised trial of the candidate ToProtocol ATP ITT

malaria vaccines FP9 METRAP and
MVA ME-TRAP among children in 1 ATP
Kenya PLoS Clin Trials
(2006)[27] (

9)
2


FFM + ME TRAP
Rabies Vaccine

?


9

2 Intention-To-

Treat ITT Per-Protocol

9
( Open Access PLoS Clinical Trials)

196

Les6-p 171-242.indd 196 4/27/11 5:23:48 PM



(CD4)





A B


2 - (t-test)

3 ANOVA

(assumption) 2



2 (independent variable)
A B

(dependent variable)

90
- ( , , A B,
)

( ,
2 , )
2
1

(nominal)
/

197

Les6-p 171-242.indd 197 4/27/11 5:23:48 PM



(ordinal)


(continuous) (gaussian
normal distribution)

(time to event)




(skew) (


)


/



(

10)

10

198

Les6-p 171-242.indd 198 4/27/11 5:23:51 PM



2


(apgar) (titre)

http://www.graphpad.com

( 2)


(

30 100
)

( Kolmogorov Smirnov test)

(parametric)

1. Parametric

Non-parametric

(
- (logarithm) )

(non-parametric statistics)

) [5,28,29]
199

Les6-p 171-242.indd 199 4/27/11 5:23:51 PM



2

,
2 ,
, (survival time)
Mean, SD Median, Proportion Kaplan-Meier
Inter-quartile range survival curve
One-sample t test Wilcoxons test Chi-square Binomial
test
Unpaired t test Mann-Whitney test Fishers test (chi- Log-rank test or
2 square for large Mantel-Haenszel
samples)
Paired t test Wilcoxons test McNemars stest Conditional
2 proportional hazards
regression
2

One-way ANOVA Kruskal-Wallis test Chi-square test Coxs proportional
3 hazard regression

Repeated Friedmans test Cochrans Q Conditional
3
measures ANOVA proportional hazards
regression

Pearson correlation Spearman Spearman correlation.
2 correlation Odds Ratio (OR)
Relative Risk (RR)
Simple linear / Simple non- Simple logistic Coxs proportional
non-linear parametric regression hazard regression
regression regression
Multiple linear/ Multiple non-linear Multiple logistic Coxs proportional
non-linear regression regression hazard regression
regression
Multivariate ANO- General Linear Mixed Multivariate Coxs
VA, General Linear Model (GLMM) proportional hazard
Mixed Model regression
(GLMM)
/ Generalized Estima- Generalized Estimation Multivariate Coxs
tion Equation (GEE) Equation (GEE) proportional hazard
regression

200

Les6-p 171-242.indd 200 4/27/11 5:23:52 PM



controlled randomized trial

PLoS Clin Trials (2007) [30]
-
(non-paramatric)
p-value 2
p-value (rofecoxib) 50 mg
(diclofenac)
50 mg 3

-
p-value





p-value
(

)
-

-
-

2

Mann-Whitney U test - (
11)
2 Doxycycline

statistical power reduces plasma VEGF-C/sVEGFR-3

and improves pathology in lymphatic
filariasis PLoS Pathog
(2006) [31]
[4,28]
1 Shortterm (lymphedema)
efficacy of rofecoxib and diclofenac
(doxy-
in acute shoulder pain: A placebo- cycline)
201

Les6-p 171-242.indd 201 4/27/11 5:23:52 PM



11

( Open Access PLoS Clinical Trials)

6 2
/


12
(paired ttest)

- (Wilcoxontest) (
Chi-square test, ttest, ANOVA
12)
2.
/


2

202

Les6-p 171-242.indd 202 4/27/11 5:23:53 PM



12

( Open Access PLoS Pathogens)

RR ( VE = 1 RR)

2 x 2

2
()
2
A B



/
2
(Relative Risk RR) chi-square
/ (Odds test 2

Ratio OR)

203

Les6-p 171-242.indd 203 4/27/11 5:23:54 PM



1
2 (strength of 2 OR RR 1
association) OR 95%CI OR RR
RR 1
2
OR RR
1 2 /
OR RR
(study
OR RR 1 design)
OR RR 16

16 2
OR RR
( Randomized Controlled Trial
RCT) cohort study
OR RR
RR
95%CI
OR RR 95%CI
OR RR
p-value case-control study
H2test 95%CI OR
RR 1 cross-sectional
study OR
p-value H2
test RR
(p-value > 0.05)
OR RR 1 RR / OR
2 OR RR

204

Les6-p 171-242.indd 204 4/27/11 5:23:54 PM



RCT
OR
RR ( (before-and-after trial)
logistic regression OR
RR) OR (ICU)
RCT 48
4
(control)
(Hazard 4
Ratio HR) RR HR
(Medical Emergency Team MET)
Cox regression



( survival
2
analysis )

[14,32,33,34] ( chi-square
1 Effect of the test) MET
medical emergency team on long-term
mortality following major surgery
Critical Care (2007) [35] odds ratio ( 13)

13 OR 2
( Open Access Critical Care)

205

Les6-p 171-242.indd 205 4/27/11 5:23:55 PM



2 Cholesterol
lowering with simvastatin improves
prognosis of diabetic patients with (RCT)
coronary heart disease. A subgroup
analysis of the Scandanavian Simvasta- (Risk
tion Study Diabetes care Ratio RR)
(1997) [36] RR
-
(simvastatin)

( RR < 1)

( 95CI RR 1)
p-value <0.05 RR
1 (
(Pooled RR = 0.94, 95CI 0.89
) ( 14) 0.98) ( 15)
3 Fracture 3.
prevention with vitamin D supplementation:

considering the inconsistent results
BMC Musculoskeletal
Disorders (2007) [37]
meta survival analysis
analysis
(/)

(/ )
()

206

Les6-p 171-242.indd 206 4/27/11 5:23:56 PM



14 RR 2
(
Diabetes Care The American
Diabetes Association)

15 RR
( Open Access BMC Musculoskeletal
Disorders)

207

Les6-p 171-242.indd 207 4/27/11 5:24:10 PM



/
5 (five-year survival probability)



2
(remission/re-infection) ()

survival time


regression
2 [7,33,34,38]
(outcome)

/ /

(step curve)
Kaplan-Meier ( 16)

16

208

Les6-p 171-242.indd 208 4/27/11 5:24:14 PM



hazard probability


2
A
B
/ 1 Mortality
and morbidity in patients receiving
1 encainide, flecanide, or placebo
(one year survival probability) The New England Journal of
A 19 Medicine. Vol.324 (1991) [39]
B 69
50 Cardiac Arrhythmia Suppression Tria
(median survival CAST

time) A 0.7 (

8 ) B 1.9 sudden death

( 1 11 ) survival

2 ( 17)
2 Safety and

Efficacy of an Attenuated Vaccine

against Severe Rotavirus Gastroenteritis

Log-rank test, Coxs proportional hazard The New England

2 Journal of Medicine. Vol.354 (2006) [40]

survival

probability G1P[8] Human Rotavirus

209

Les6-p 171-242.indd 209 4/27/11 5:24:14 PM



17

2
( New England Journal of Medicine

Massachusetts Medical Society)

HRV 3 1.
severe gastroenteritis

hazard

(dose) (subgroup)
2

( 18)

/







data
dredging data trawling

210

Les6-p 171-242.indd 210 4/27/11 5:24:15 PM



18

2
( New England Journal of Medicine

Massachusetts Medical Society)

- / (biologi-
cal/clinical rationale)



- (prior
5 100 evidence/belief)

(pilot
study)

[14,18,

41,42]

211

Les6-p 171-242.indd 211 4/27/11 5:24:17 PM



- (statistical

evidence)

-


( power



)











/
-

(independent con-
firmation) -





/

212

Les6-p 171-242.indd 212 4/27/11 5:24:17 PM



HIV 3
-

( 19)

2 Randomised
trial of home-based psychological
- nursing intervention for patients
recovering from myocardial infarction
Lancet, Vol. 350 (2002)

Subgroup

Analysis, Covariate adjustment and
/
baseline comparisons in clinical trial

reporting: Current practice and
problems. [Statistics in Medicine,
Vol.21 (2002)] [44]

1 Under-

standing the results of AIDSVAX

Trial AIDS Vaccine -
Advocacy Coalition (AVAC) (2004) [43] /

213

Les6-p 171-242.indd 213 4/27/11 5:24:18 PM



19

( VaxGen)

()

(

20)
p-value 3 Prevention
=0.064
of heart failure by antihypertensive

drug treatment in older persons with
(interaction)

isolated systolic hypertension

Journal of the American

Medical Association, Vol.278 (1997)
22 12 (OR=
2.0) Subgroup
2 Analysis, Covariate adjustment and
11 11 (OR=1.0) baseline comparisons in clinical trial
interaction OR reporting: Current practice and
2 (-) problems. [Statistics in Medicine,
p=0.21 Vol.21 (2002)] [44]

214

Les6-p 171-242.indd 214 4/27/11 5:24:19 PM



20

( Statistics in Medicine John Wiley &
Sons, Ltd)

RR
RR ( 95CI)
2 MI ( yes)
Myocardial 1892
Infarction MI ( yes vs. no) ()
5 17
(active vs. placebo) interaction
MI ( yes) 2 p=0.24

RR (/ MI)
(active
yes) (placebo yes) /
76 33 ( 21)

215

Les6-p 171-242.indd 215 4/27/11 5:24:20 PM



21
( Statistics in Medicine John Wiley &
Sons, Ltd)

2.


/

/ (baseline)

(change from
baseline)

216

Les6-p 171-242.indd 216 4/27/11 5:24:22 PM



( baseline )
(demographic

)
(precise) [14,15,32,33]
(personal characteristics

, /


) (study
- p-value site)



(adjusted/controlled for)

(covariables)

(unbiased

estimate)

(confidence interval) ANCOVA (Analysis

of Covariance), Stratified Analysis

(Mentel-Haenszel), Multiple Logistic
/ Regression, Cox-Reported Hazard
Regression
-

Toremifene
and tamoxifen are equally effective for
early-stage breast cancer: first results

217

Les6-p 171-242.indd 217 4/27/11 5:24:22 PM



of International Breast Cancer Study ER positive ER negative)

Group Trials 12-93 and 14-93
Annals of Oncology, Vol.15 (2004) [45] (p-value )
(p-value )
2 (tore-
mifene) (tamoxifen))
(tumor)
disease-free survival RR p-value
time / (
( estrogen receptor, 22)
22
( Annals of Oncology Oxford University

Press)

218

Les6-p 171-242.indd 218 4/27/11 5:24:25 PM



3.
H 0
(p-value) p=0.05
5



[14]

3

(multiple

null hypotheses)

H0 p-value
1
p-value < 0.05 Type I error 0.05
1 5% 0.0500
2 10% 0.0253
3 14% 0.0170
4 19% 0.0127
5 23% 0.0102
10 40% 0.0056
20 64% 0.0026
50 92% 0.0010
100 99% 0.0005
N 100 (1.00 0.95N) 1.00-0.95(1/N)

219

Les6-p 171-242.indd 219 4/27/11 5:24:25 PM



1 Medroxy-
progesterone improves nocturnal
breathing in postmenopausal women
H0 0.05 with chronic obstructive pulmonary
/ H0 disease Respiratory
0.05 Research (2005) [46]
3 H0
/ H0 (singleblinded)

0.05

14 15
1
2

Medroxy Progesterone Acetate

3 0.05 MPA 2
3
H0 p-value H0 0.017 4
S1, S2, SWS (Slow Wave Sleep)
Rapid Eye Movement REM
(multiple comparisons)

(SaO2 )

p-value

p-value

Bonferroni

adjustment ( 23)
( ) 2 Effects of
(interim analysis) glaucoma drugs on ocular hemody-

namics in normal tension glaucoma: a
(final analysis)
randomized trial comparing bimatoprost
[38,42] and latanoprost with dorzolamide

220

Les6-p 171-242.indd 220 4/27/11 5:24:25 PM



23 Bon-

ferroni
( Open Access Respiratory Research)

BMC Ophthalmology
(2005) [47] (hemodynamics) Peak Systolic
Velocity PSV End Diastolic
Velocity EDV

1 3 2
(bimatoprost), 4
(latanoprost), 8
(dorzalamide) pvalue
(negative 0.05
control) 1 pvalue Bonferroni

221

Les6-p 171-242.indd 221 4/27/11 5:24:27 PM



p <0.006 ( 2 )
(SAP)

PSV
( ) /
pvalue <0.001 EDV

p=0.04 p=0.02
( 24)
4.





ICH guideline [1,25] [4,14,38,41]

24
Bonferroni
( Open Access BMC Ophthalmology)

222

Les6-p 171-242.indd 222 4/27/11 5:24:42 PM



Last Observation Carried Forward Missing
LOCF Completely At Random MCAR,
Missing At Random MAR
non-random/non-ignorable missing-
(placebo-controlled su- ners at random

periority trial)

non-
LOCF ignorable


(H 0) (multiple imputations)

LOCF ITT PP




1 A clinical
trial of the use of Sibutramine for

(mean imputation) the treatment of patients suffering

(regression essential obesity
imputation) International Journal of Obesity, Vol.24
ITT (2000) [48]

(sibutramine)

223

Les6-p 171-242.indd 223 4/27/11 5:24:43 PM



Complex Regional Pain syndrome

type 1 BMC Neurology

(2004) [49]
day-15, day 0, day 30,
day 60, day 90, day 120, day 10,
day 180 (gabapentin)
2 ITT ( 3
6 ) 3
(wash out)
LOCF. 2
(VAS)
( 12
25)
2 Randomised
controlled trial of gabapentin in

25

LOCF
( International Journal of Obesity Nature

Publishing Group)

224

Les6-p 171-242.indd 224 4/27/11 5:24:45 PM



4 (open-label)

(proof-of-concept)
(17 )
Hydroxyurea
( (HU) 3
26)
3 Abacavir, ( HIVRNA
efavirenz, didanosine, with or without 400 copies/ml
hydroxyurea, in HIV-infected adults 16
failing initial nucleoside/protease ) (primary efficacy
inhibitor-containing regimens endpoints)
BMC Infectious Diseases HIVRNA <400 copies/ml
(2005) [50] 24 48

26

( Open Access BMC Neurology)

225

Les6-p 171-242.indd 225 4/27/11 5:24:46 PM



(secondary efficacy endpoints) ITT

<50 copies/ (ITT:observed analysis)

ml

Intention-To-Treat
24 48

ITT ITT 2

Mantel Haenzel Test (

(ITT:Missing = 27)
treatment failure analysis)

(subgroup analysis)

HU HU


24
8
48


CD4 ( 28)
27

2 (:

: )
( Open Access BMC Infectious
Diseases)

226

Les6-p 171-242.indd 226 4/27/11 5:25:06 PM



28

( Open Access BMC Infectious
Diseases)

-


(outlier) (lot)

- -

227

Les6-p 171-242.indd 227 4/27/11 5:25:12 PM



(guassian/

normal distribution)

2
[14,15,32,38]

- /

(-)

4 Supervised
( versus unsupervised antimalarial

treatment with six-dose artemether-
) lumefantrine: pharmacokinetic and
dosage-related findings from a clinical
trial in Uganda Malaria
Journal (2006) [51]

228

Les6-p 171-242.indd 228 4/27/11 5:25:12 PM



(Plas-
modium falciparum)
- (Artemeter (missing)
Lumefantrine A/L)

3 7
(lumefan- ( 29)
trine concentration) 2
5.

(supervised)

29

( Open Access Malaria Journal)

229

Les6-p 171-242.indd 229 4/27/11 5:25:14 PM



(scale)

101001000

log(10)log(100)...log(1000)

123
10 1, 2, 3

10
(skew
curve)
(

) ( 4)
30





( titre)

-

(log)
A B



(non-normal non-guassian
abnormal)
30 ()

[5,23,28]

(count) (value)

230

Les6-p 171-242.indd 230 4/27/11 5:25:14 PM



30 () (synergistic interaction)
(ketamine)
(opioids)
(count) (value)
10


10 10
1 Investiga-
tion of the potentiation of the
analgesic effects of fentanyl by 5 5
ketamine in humans: a double-blinded,
randomised, placebo controlled,
crossover study of experimental pain

BMC Anesthesiology (Subjective Sedation
(2005) [52] VAS)

(crossover)

231

Les6-p 171-242.indd 231 4/27/11 5:25:16 PM



30

()

()

232

Les6-p 171-242.indd 232 4/27/11 5:25:42 PM



HIV RNA concentration (

2 ) arm 2 arm 3
( 31) 0.5 log10 copies/ml
2 Combina- (baseline)
tion Therapy With Stavudine (d4T) 12 48
Plus Didanosine (ddI) in Children With
Human Immunodeficiency Virus log 10
Infection Pediatrics, ( 32)
Vol. 103 (1999) [53] 3 ART sup-
presses plasma HIV-1 RNA to a stable
2 (phase II) set point predicted by pretherapy
viremia PLoS Pathog
3 (study arms) (2007) [54]

power= 80 (
power ) HIV1 RNA

Plasma 130

31

( Open Access BMC
Anesthesiology)

233

Les6-p 171-242.indd 233 4/27/11 5:25:43 PM



32 log 10

( Pediatrics American Academy of
Pediatrics)

4

24
pearson correlation

R2
(linear regression)

( 33) (data transformation)
4 Managing
an effective treatment for neuroleptic
malignant Syndrome -
Critical Care (2007) [55]

Neuro-
leptic Malignant Syndrome NMS
( 34)

234

Les6-p 171-242.indd 234 4/27/11 5:25:45 PM



33 log 10

( Open Access PLoS Pathogens)

Figure 3. Correlation between Pretherapy and On-Therapy Viral RNA Levels

34

( Open Access Critical Care)

235

Les6-p 171-242.indd 235 4/27/11 5:25:47 PM



Biomed Central PLoS

/
Open Access /

1. US FDA. Guidance for Industry:
(E9) Statistical Principles for Clini-
cal Trails; September,1998.

2. Topol EJ, Moliterno DJ, Herrmann

HC, et al. TARGET I: Do Tirofiban

and ReoPro Give Similar Efficacy

Trial. Comparison of two platelet
(peer-
glycoprotein IIb/IIIa inhibitors,
review journal)
tirofiban and abciximab, for the

prevention of ischemic events

with percutaneous coronary revas-

cularization. N Engl J Med. 2001;
:
344:1888-1894.

[56,57] 3. US FDA Guidance for Industry: (E8)
// General Considerations for Clinical
Open Access Trials;1999.

236

Les6-p 171-242.indd 236 4/27/11 5:25:47 PM


4. British Medical Journal. Statistics
at Square One. Available from:
http://www.bmj.com
5. Daniel WW. Biostatistics: A Foun-
dation for Analysis in the Heath
Sciences (5th Ed.) New York: John
Wiley & Sons;1991.
6. Diggle PJ, Liang KY, Zeger SL.
Analysis of longitudinal data.
Oxford:Oxford University Press;
1996.
7. Peace KE. Design and analysis
of clinical trials with time-to-
event endpoints. New York:CRC
Press;2009.
8. Burton P, Gurin L, Sly P. Extending
the simple linear regression model
to account for correlated responses:
on introduction to generalized es-
timating equation techniques and
multi-level mixed modeling. Stat
Med.1998; 17:1261-1291.
9. Albert Ps. Longitudinal data analy-
sis (reported measures) in clinical
trials. Stat Med.1998;8:1707-1732.
10. Karamursel, E, et.al. A Randomized
Trial of Low-Dose, Topical Mitomy-
cin-C in the Treatment of Severe
Vernal Keratoconjunctivitis. Oph-
thalmology. 2000; 107(2):263-269.
Les6-p 171-242.indd 237
11. Richter KS, Davis A, Carter J,
Greenhouse SJ, et.al. No advantage
of laser-assisted over conventional
intracytoplasmic sperm injection: a
randomized controlled trial. Journal
of Experimental & Clinical Assisted
Reproduction. 2006; 3:5[7pp.].
Available from: http://www.jexpeli-
nassistreprod.com/content/3/1/5
12. Hollisaz MT, Khedmat H, Yari F. A
randomized clinical trial compar-
ing hydrocolloid, phenytoin and
simple dressings for the treatment
of pressure ulcers. BMC Derma-
tology 2004; 4:18[9pp.]. Available
from: http://www.biomedcentral.
com/1471-5945/4/18.
13. Fretheim A, Oxman AD, Havelsrud
K, Treweek S, Kristoffersen DT, et
al. (2006) Rational Prescribing in
Primary Care (RaPP): A cluster
randomized trial of a tailored inter-
vention. PLoS Med. 2006; 3(6):0783-
0791.
14. Chow SC & Liu J. Design and
Analysis of Clinical Trails: Concept
and methodologies. New York:
John Wiley & Sons, Inc;1998.
15. DAgastino, RB & Massaro JM.
New Developments in Medical
237
4/27/11 5:25:47 PM

Clinical Trials. Journal of Dental
Research. 2004; 83:c18-c24.
16. Fukuda H & Ohashi Y. A guideline
for reporting results of statistical
analysis in Japanese Journal of
Clinical Oncology, Available from:
http://www.info.ncc.go.jp
17. Meinert CL. & Tonasia S. Clinical
Trials Design, Conduct and Analy-
sis. New York: Oxford University
Press; 1986.
18. Gebski VJ & Keech AC. Statistical
Methods in Clinical Trails. MJA.
2003; 178(4):182-184.
19. DeMets DL, Furberg CD, Friedman
LM. Dot Monitoring in clinical tri-
als. New York:Springer; 2006.
20. Creative Research Systems. Statis-
tical Significance. Available from:
http://www.surveysystem.com
21. Henkel RE. Tests of Significance.
London: SAGE Publications; 1976.
22. Denegar C.R. What does sig-
nificance mean? Available from:
http://www.ppta.org
23. Motulsky H. Intuitive Biostatistics.
New York: University Press, 1995.
Available from: http://www.graph-
pad.com
238
Les6-p 171-242.indd 238
24. Vamvakas EC. Rationale, Objec-
tives and Interpretation of Rand-
omized Controlled Trials. Journal of
Clinical Apheresis. 1997; 12(3):130-
139.
25. USFDA Guideline for Industry [E3]
Structure and Content of Clinical
Study Report; 1996.
26. Hollis S & Campbell.F. What
is meant by intention to treat
analysis? Survey of published
randomised controlled trials. BMJ.
1999; 319:670-374.
27. Bejon P, Mwacharo J, Kai O, Mwan-
gi T, Milligan P, et al. A phase 2b
randomised trial of the candidate
malaria vaccines FP9 METRAP and
MVA ME-TRAP among children in
Kenya. PLoS Clin Trials 2006; 1(6):
e29, 0001-0010.
28. Conover WJ. Practical Non-para-
metric Statistics. (2nd Ed.) New
York: John Wiley & Sons; 1980.
29. Fleiss JL. Statistical Methods for
Rates and Proportions. (2nd Ed.)
New York: John Wiley & Sons;
1981.
30. Dougados M, Le Henanff A, Logeart
I, Ravaud P Shortterm efficacy of
4/27/11 5:25:48 PM

rofecoxib anddiclofenac in acute
shoulder pain: A placebo-controlled
randomized trial. PLoS Clin Trials.
2007; 2(3): e9,0001-0009.
31. Debrah AY, Mand S, Specht S,
Marfo-Debrekyei Y, Batsa L, et
al. Doxycycline reduces plasma
VEGF-C/sVEGFR-3 and improves
pathology in lymphatic filariasis.
PLoS Pathog. 2006; 2(9);e92,0829-
0843.
32. Newman SC. Biostatistical Meth-
ods in Epidemiology. New York:
Wiley-Interscience; 2001.
33. Kleinbaum DG, Kupper KL. Applied
Regression Analysis and Other
Multivariable Methods. California:
Wadsworth Publishing Co.,Ltd.;
1978.
34. Lee, ET. Statistical Methods for
Survival Data Analysis. (2nd Ed.)
New York: John Wiley & Sons;
1992.
35. Jones D, Egi M, Bellomo R, Gold-
smith D. Effect of the medical
emergency team on long-term
mortality following major surgery.
Critical Care. 2007; 11:R12[11pp.].
Available from: http://www.cofo-
rum.com/content/11/1/R12.
Les6-p 171-242.indd 239
36. Pyorala K, Pederson TR, Kjekshus J,
Faergeman O, e.al. Cholesterol low-
ering with simvastatin improves
prognosis of diabetic patients with
coronary heart disease. A subgroup
analysis of the Scandanavian Sim-
vastation Study. Diabetes Care,
1997; 20(4):614-620.
37. Izaks GJ. Fracture prevention
with vitamin D supplementation:
considering the inconsistent re-
sults. BMC Musculoskeletal Dis-
orders 2007; 8:26[8pp.]. Available
from: http://www.biomedcentral.
com/1471-2474/8/26
38. Senn S. Statistical Issues in Drug
Development. New York:John-
Wiley & Sons, Inc.;1997.
39. Echt DS, et.al. Mortality and
morbidity in patients receiving
encainide, flecanide, or placebo.
New England Journal of Medicine.
1991;324:781-788.
40. Guillermo M, et.al. Safety and Ef-
ficacy of an Attenuated Vaccine
against Severe Rotavirus Gastro-
enteritis. New England Journal of
Medicine, 2006;354:11-22.
41. Elkwood M. Critical Appraisal of
Epidemiological Studies and Clini-
239
4/27/11 5:25:48 PM

cal Trials. Oxford:Oxford University
Press;2007.
42. Piantadosi S. Clinical Trials: A
Methodological Perspective. New
York: Wiley-Interscience; 2005.
43. AIDS Vaccine Advocacy Coalition
(AVAC). Understanding the results
of AIDSVAX Trial (2004). Available
from: http://www.avac.org
44. Pocock SJ et.al. Subgroup Analysis,
Covariate adjustment and base-
line comparisons in clinical trial
reporting: Current practice and
problems. Statistics in Medicine.
2002; 21:2917-2930.
45. International Breast Cancer Study
Group1. Toremifene and tamoxifen
are equally effective for early-stage
breast cancer: first results of In-
ternational Breast Cancer Study
Group Trials 12-93 and 14-93. An-
nals of Oncology. 2004; 15(12):1749-
1759.
46. Saaresranta T, Aittokallio T, Utriain-
en K, Polo O. Medroxyprogesterone
improves nocturnal breathing
in postmenopausal women with
chronic obstructive pulmonary
disease. Respiratory Research
240
Les6-p 171-242.indd 240
2005, 6:28[12pp.]. Available from:
http://respiratory-research.com/
com/content/6/1/28
47. Zeitz O, Matthiessen ET, Reuss J,
Wiermann A, et.al. Effects of glau-
coma drugs on ocular hemodynam-
ics in normal tension glaucoma:
a randomized trial comparing
bimatoprost and latanoprost with
dorzolamide. BMC Ophthalmol-
ogy 2005; 5:6[11pp.]. Available
from: http://www.biomedcentral.
com/1471-2415/5/6
48. Fanghanel1 G, et.al. A clinical
trial of the use of Sibutramine for
the treatment of patients suffering
essential obesity. International
Journal of Obesity. 2000; 24(2):144-
150.
49. van de Vusse AC, Stomp-van
den Berg S, Kessels A, Weber W.
Randomised controlled trial of
gabapentin in Complex Regional
Pain Syndrome type 1. BMC Neu-
rology 2004; 4:13[9pp.]. Available
from: http://www.biomedcentral.
com/1471-2377/4/13
50. Swindells S, Cohen CJ, Berger DS,
Tashima KT, et.al. for the NZTA4008
Study Team. Abacavir, efavirenz,
4/27/11 5:25:48 PM

didanosine, with or without
hydroxyurea, in HIV-infected adults
failing initial nucleoside/protease
inhibitor-containing regimens.
BMC Infectious Diseases 2005;
5:23[13pp.]. Available from: http://
ww.biomedcentral.com/1471-
1334/5/23
51. Checchi F, Piola P, Fogg C, Baju-
nirwe F, et.al. Supervised versus
unsupervised antimalarial treat-
ment with six-dose artemether-
lumefantrine: pharmacokinetic
and dosage-related findings from
a clinical trial in Uganda. Malaria
Journal. 2006; 5:59[8pp.]. Available
from: malariajournal.com/con-
tent/5/1/59
52. Tucker AP, Kim Y, Nadeson R,
Goodchild CS. Investigation of the
potentiation of the analgesic effects
of fentanyl by ketamine in humans:
a double-blinded, randomised, pla-
cebo controlled, crossover study of
experimental pain. BMC Anesthe-
siology 2005, 5:2[12[[.]. Available
from: http://www.biomedcentral.
com/1471-2253/5/2
53. Kline MW, et.al. Combination
Therapy With Stavudine (d4T) Plus
Les6-p 171-242.indd 241
Didanosine (ddI) in Children With
Human Immunodeficiency Virus
Infection. Pediatrics, Vol. 103, 1999;
103(5)[6pp.]. Available from: http://
www.pediatrics.org/cgi/content/
full/105/e62#otherarticles
54. Maldarelli F, Palmer S, King MS,
Wiegand A, Polis MA, et al. ART
suppresses plasma HIV-1 RNA
to a stable set point predicted by
pretherapy viremia. PLoS Pathog.
2007;3(4):e46, 0484-0488.
55. Reulbach U, Dtsch C, Biermann
T, Sperling W, et.al. Managing an
effective treatment for neuroleptic
malignant Syndrome. Critical Care
2007; 11:R4[6pp.]. Available from:
http://ceforum.com/content/11/1/
R4
56. -
FAQ
( 1)
2544; 30(3):227-235.
57. -
FAQ
( 2)
2545; 31(1):49-62.
241
4/27/11 5:25:49 PM


Les6-p 171-242.indd 242 4/27/11 5:25:49 PM