maxime dougados paris-descartes university, medicine faculty; upres ea-4058; ap-hp, cochin hospital,...
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Maxime DOUGADOSParis-Descartes University, Medicine Faculty; UPRES EA-4058;
AP-HP, Cochin Hospital, Rheumatology B DptPARIS, France
Status versus Changes:
Feeling Good versus Feeling Better
Status versus Changes: Feeling Good versus Feeling Better
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Placebo
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-1 0 1 2 3 4 5 6
Placebo
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-1 0 1 2 3 4 5 6
Placebo
Variable PAIN (VAS 0-100)P
ain
Patient #1
Placebo
Placebo Placebo Placebo Placebo Placebo Placebo
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-1 0 1 2 3 4 5 6
Placebo0 1 2 3 4 5 6 months
(60)
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Pai
n
Patient #2
0 1 2 3 4 5 6 months
(60)
30
Pai
n
Patient #3
0 1 2 3 4 5 6 months
(60)
30
Pai
n
Patient #4
0 1 2 3 4 5 6 months
(60)
30
100
0
100
0
100
0
100
0
=50 =50
=50 =50
Status versus Changes: Feeling Good versus Feeling Better
Points to consider
a) How to present the results
b) How to switch a continuous variable into a dichotomous variable?
c) How to evaluate the clinical relevance of the technic of reporting?
Status versus Changes: Feeling Good versus Feeling Better
Points to consider
a) How to present the results
b) How to switch a continuous variable into a dichotomous variable?
c) How to evaluate the clinical relevance of the technic of reporting?
Status versus Changes: Feeling Good versus Feeling Better
Responder: change in VAS (0-100) during the study >MCII (Minimum Clinically Important Improvement)
Remission/satisfied: absolute value of VAS (0-100) at the end of the study <PASS (Patient Acceptable Symptom State)
0 1 2 3
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Placebo Active
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Placebo Active
Continuous variablemean change
Binary variable(changes)
Binary variable(status)
weeks
Pai
n (
0-1
00 m
m V
AS
)
% r
e sp
on
de r
s *
% s
a ti s
fied
/ re
mis
s io
n**
Placebo
Active
How to present the results
Status versus Changes: Feeling Good versus Feeling Better
Technics of reporting
Mean changes versus percentage patients
It’s good to feel better but it’s better to feel good
It’s better to feel better/good AS SOON AS POSSIBLE
It’s even better to feel better/good as soon as possible and FOR AS LONG AS POSSIBLE
It’s good to feel better/good for as long as possible
Percentage patients
Status versus Changes: Feeling Good versus Feeling Better
Presentation of continuous variables Table (example: NSAID in painful shoulder*)
Figure (example: TICORA trial**)
*Dougados M et al. Plos Clin trials2007,2(3),e9**Grigor C et al. Lancet, 2004;364:263-9
6.9
3.5
Treatment group Baseline Changes
Active 68 14 -38 26
Placebo 68 14 -27 25
0
1
2
3
4
5
6
0 3 6 9 12 15 18
Group A = "routine"Group B = "DAS"
DA
S
Groupe A = traitement selon les habitudes du rhumatologue (« pratique quotidienne »)
Groupe B = traitement selon les résultats du DAS (« pratique guidée »)
Status versus Changes: Feeling Good versus Feeling Better
Presentation of dichotomous variables
65
22
0
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40
60
80
100
Placebo Rituximab
2 150
20
40
60
80
100
Placebo Rituximab
To feel better To feel good
EU
LA
R r
esp
on
der
s %
pat
i en
ts*
DA
S <
3. 2
%
pat
i en
ts
*Cohen SB et al. Arthritis Rheum 2006;2793-806
It’s good to feel better but it’s better to feel good (example: Rituximab versus placebo in RA: REFLECT study)
Status versus Changes: Feeling Good versus Feeling Better
Presentation of dichotomous variablesIt’s better to feel better/good as soon as possible
(example: TEMPO trial).
Copyright ©2006 BMJ Publishing Group Ltd.
van der Heijde, D et al. Ann Rheum Dis 2006;65:328-34
Figure 3 Kaplan-Meier estimation of time to HAQ disability scores & lt; =0.5 and sustained for 6 months.
Status versus Changes: Feeling Good versus Feeling Better
Presentation of dichotomous variables
It’s even better to feel better/good as soon as possible for AS LONG AS POSSIBLE (example: NSAIDs versus placebo in acute shoulder pain).
Dougados M et al. Plos Clin trials2007,2(3),e9
0
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-1 0 1 2 3 4 5 6 7
Placebo
Active
Su
cc
es
s*
* % patients with a pain VAS <30 over time
p=0.0027
0
20
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100
-1 0 1 2 3 4 5 6 7
Placebo
Active
Su
cc
es
s*
* % patients with a sustained pain VAS <30
p=0.0036
Status versus Changes: Feeling Good versus Feeling Better
Presentation of dichotomous variables
It’s good to feel better/good for AS LONG AS POSSIBLE.
% patients with a « success » during 2 or 3 consecutive visits.
% patients with a « success » during 6 consecutive monthly visits in a one/two years trial.
ConRew Scores
Status versus Changes: Feeling Good versus Feeling Better
Presentation of continuous variables
0
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-1 1 3 5 7 9 11Placebo
Patient #x
0 1 2 3 4 5 6 7 8 9 10 11 12 months
100
0
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Evaluation of patient #xMajor Clinical Response (FDA proposal)MCR = yes if success at 6 consecutive visits
x x x x x x x = YESCon Rew System
Unweighted 0 I I 0 I I I I I I I 0 I = I0
Weighted 1 0 I I+I 0 I+I I+I I+I I+I I+I I+I I+I 0 I = I7
Weighted 2 0 I I+I 0 I I+I I+2 I+3 I+4 I+5 I+6 0 I = 32
Status versus Changes: Feeling Good versus Feeling Better
1.71.9
4.4
0
5
0 1 2 3 4
23.8
9.95.7
0
50
MTX ETN ETN + MTX
AC
R2
0- M
CR
(% p
ati
en
t s)
It’s good to feel good/better for as long as possible(example: TEMPO trial*)
Co
n R
ew
Un
we
i gh
t ed
(% p
ati
etn
s)
Co
n R
ew
We
i gh
ted
1.01.1
2.4
0
5
0 1 2 3 4MTXn = 228
ETNn = 223
ETN + MTXn = 231
MTXn = 228
ETNn = 223
ETN + MTXn = 231n = 228 n = 223 n = 231
*van der Heijde D et.al. Ann Rheum Dis 2006;64:1582-7
Status versus Changes: Feeling Good versus Feeling Better
Points to consider
a) How to present the results
b) How to switch a continuous variable into a dichotomous variable?
c) How to evaluate the clinical relevance of the technic of reporting?
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
Doctor’s perspective
Patient’s perspective
Trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
Doctor’s perspective
Patient’s perspective
Trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
Trialist’s perspective
Objective: to propose a cut-off which takes into accountthe variability of the technic.
Methods: Bland & Altman (Smallest Detectable Difference)
Status versus Changes: Feeling Good versus Feeling Better
Smallest Detectable Difference (SDD) orMinimal Individual Difference (MID)*
Patient1....
30
*Bland & Altman, Lancet 1986;i:307-10.
Analysis 1a1
.
.
.
.x1
Analysis 2a2
.
.
.
.x2
Delta(a1 -a2)
m(x1-x2) ± SD (x1-x2)
How to switch a continuous into a dichotomous variable?
Trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
-2
-1,5
-1
-0,50
0,5
1
1,5
2
0 1 2 3 4 5 6
Mean-2SD
Mean+2SD
Mean
Mean JSW (mm)
Smallest Detectable Difference
Example: Radiological hip joint space width
*Auleley GR…Dougados M, Ann Rheum Dis, 2000;59:422-7
How to switch a continuous into a dichotomous variable?
Trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
Doctor’s perspective
Patient’s perspective
Trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
Doctor’s perspective
Objective: to propose a cut-off which takes into accountthe capacity to predict a « hard » end-point.
Methods: - Longitudinal study- R.O.C. technic
Status versus Changes: Feeling Good versus Feeling Better
Example: Radiological hip joint space width (mm)*
Study design:
X-rays:
Requirement to THR:
N = 384ROC curve analysis
/ / / / / / / / / / / / / / / / /
Years 0 2 5
Years 0 2 5
*Maillefert JF, …, Dougados M. Rheumatology (Oxford) 2002;41:142-7
How to switch a continuous into a dichotomous variable?
Doctor’s perspective(Predictive validity)
Status versus Changes: Feeling Good versus Feeling Better
0 m m- 0 . 1 m m- 0 . 2 m m- 0 . 3 m m- 0 . 4 m m
- 0 . 5 m m
- 0 . 6 m m
- 0 . 7 m m- 0 . 8 m m- 1 m m
- 1 . 1 m m
- 1 . 3 m m
706050403020100
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0
Doctor’s perspective (Predictive validity)Example: Radiological hip joint space width (mm)*
Se = % patients with a change in JSW (mm) over a specific cut-off between baseline and year 2 requiring a Total Hip Replacement between year 2 and year 5.
1-Spe = % patients with a change in JSW (mm) below a specific cut-off between baseline and year 2 not requiring a Total Hip Replacement between year 2 and year 5.
Ab
solu
te c
han
ges
in
JS
W b
etw
een
b
asel
ine
and
2 y
ear
foll
ow
-up
Sensitivity (%)
1- specificity
How to switch a continuous into a dichotomous variable?
*Maillefert JF, …, Dougados M. Rheumatology (Oxford) 2002;41:142-7
Status versus Changes: Feeling Good versus Feeling Better
Pat
i en
ts w
i th
ou
t T
HA
(%
)
Time from baseline (months
Decrease in JSW ≤ 0.4 mm
Decrease in JSW > 0.4 mm
Example: Radiological hip joint space width (mm)*
Patients with a radiological JSW change over 0.4 mm between baseline and year 2 (n = 171).
Patients with a radiological JSW change below 0.4 mm between baseline and year 2 (n = 213).
6050403020100
100
90
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50
40
30
20
1
How to switch a continuous into a dichotomous variable?Doctor’s perspective (Predictive validity)
*Maillefert JF, …, Dougados M. Rheumatology (Oxford) 2002;41:142-7
Status versus Changes: Feeling Good versus Feeling Better
Number ofpatients
X-rays (Change in joint space width: mm)
N = 423
0
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120
160
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240
+0,4 0,0 -0,4 -0,8 -1,0 -1,4 -1,8 -3,0
How to switch a continuous into a dichotomous variable?Example: change in JSW in hip OA
Status versus Changes: Feeling Good versus Feeling Better
% patients
RadiologicalprogressionYES
n = 90NO
n = 333
0
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100
How to switch a continuous into a dichotomous variable?
Example: change in JSW in hip OA
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
Doctor’s perspective
Patient’s perspective
Trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
Patient’s perspective
Objective: to propose a cut-off which takes into accountthe patient’s opinion.
Methods: • Study design• Cross-sectional (PASS)• Longitudinal (MCII)
• Technic• R.O.C.• 75th percentile
Status versus Changes: Feeling Good versus Feeling Better
Determination of the optimal cut-offs in changes in changes (MCII) and/or absolute values (PASS) in symptomatic OA variables
Status versus Changes: Feeling Good versus Feeling Better
4 weeks duration
Baseline – final visits
At baseline and final visits, outcome measures
At final visit, « gold standard » questions
Pain Function Global
Improvement Status
MCII - PASS
Patient’s perspective
Status versus Changes: Feeling Good versus Feeling Better
Aspects of the cumulative distribution function used to determine the PASS (pain scores in patietns with knee OA)
Status versus Changes: Feeling Good versus Feeling Better
*Tubach F, …, Dougados M et al. Ann Rheum Dis 2005;64:28-33,34-7
Low rate Intermediate tertile High tertile
Pai
n V
AS
How to evaluate the clinical relevance of the technic of reporting?Responder versus Status: the patient’s perspective
Status versus Changes: Feeling Good versus Feeling Better
*Tubach F, …, Dougados M et al. Ann Rheum Dis 2005;64:28-33,34-7
How to evaluate the clinical relevance of the technic of reporting?Responder versus Status: the patient’s perspective
Low rate Intermediate tertile High tertile
Pai
n V
AS
Baseline value – MCII = PASS
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting?Responder versus Status: the patient’s perspective
*Tubach F, …, Dougados M et al. Ann Rheum Dis 2005;64:28-33,34-7
MCII
PASS
Baseline absolute value
Status versus Changes: Feeling Good versus Feeling Better
Points to consider
a) How to present the results
b) How to switch a continuous variable into a dichotomous variable?
c) How to evaluate the clinical relevance of the technic of reporting?
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting?
The doctor’s perspective
The patient’s perspective
The trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting?
The doctor’s perspective
The patient’s perspective
The trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting?
Objective: To decrease the number of patients to be recruited in a trial.
Methods: Sample size calculation based on the proposed technic of reporting
The trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting?
= 5%, = 10%, two tailed test
Expected placebo effect: the one observed in a previous trial with the proposed technic of reporting.
Expected active effect: the one observed in a previous trial with the proposed technic of reporting.
The trialist’s perspective(Number Need to Study)
The lowest NNS, the highest value of the technic.
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting? The trialist’s perspective
(NNS: Number Need to Study)(example: AIM trial*)
*Dougados M et al., Ann Rheum Dis 2009;68:484-9
Technic of reporting L.R.+DAS28-CRP-AUC 23
% responders (ACR20)) 69
% good condition (DAS < 3.2) 71
Time to better (ACR20) condition 71
Time to good (DAS < 3.2) condition 113
Time to sustained better (ACR20) condition 39
Time to sustained good (DAS < 3.2) condition 57
Durability (unweighted Con Rew) 79
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting?
The doctor’s perspective
The patient’s perspective
The trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable?
The doctor’s perspective(predictive validity)
Objective: to predict a subsequent « hard » end-point.
Methods: • Longitudinal study
• Technic: Likelihood ratio: Se/1-Spe
Successyes/no
Radiological progressionyes/no
Status versus Changes: Feeling Good versus Feeling Better
Example: AIM trial
AnalysisRadiological progression at year 1
yes no
yes a b
no c d
Su
cces
s at
mo
nth
6
The highest L.R.+, the highest value of the technic
Radiological progression: changes after 1 year
Success at 6 months
Se = a/a+cSpe = d/b+dL.R. + = Se/1-Spe
The doctor’s perspective(predictive validity)
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting? The doctor’s perspective
(capacity to predict a subsequent radiological progression)(example: AIM trial*)
Technic of reporting L.R.+
DAS28-CRP-AUC 0.54
% responders (ACR20)) 0.94
% good condition (DAS < 3.2) 1.37
Time to better (ACR20) condition 1.11
Time to good (DAS < 3.2) condition 1.30
Time to sustained better (ACR20) condition 1.24
Time to sustained good (DAS < 3.2) condition 1.34
Durability (unweighted Con Rew) 1.31
*Dougados M et al., Ann Rheum Dis 2009;68:484-9
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting?
The doctor’s perspective
The patient’s perspective
The trialist’s perspective
Status versus Changes: Feeling Good versus Feeling Better
How to switch a continuous into a dichotomous variable? The patient’s perspective
(face validity)
Objective: to correlate with the patient’s opinion.
Methods: • Longitudinal study
• Technic: Likelihood Ratio
Successyes/no
Patient’s good conditionyes/no
Status versus Changes: Feeling Good versus Feeling Better
Patient’s opinion: at month 6, SF36 question #1: « in general, would you say that your health is poor, fair versus good, very good, excellent »
Patient’s good condition at month 6
yes no
yes a b
no c d
Su
cces
s a
t m
on
th 6
The highest L.R.+, the highest value of the technic
The patient’s perspective(capacity to correlate with the patient’s opinion)
Example: AIM trial
Evaluation:
Se = a/a+cSpe = d/b+dL.R.+ = Se/1-Spe
Status versus Changes: Feeling Good versus Feeling Better
How to evaluate the clinical relevance of the technic of reporting? The patient’s perspective
(capacity to correlate with the patient’s opinion)(example: AIM trial*)
*Tubach F, …, Dougados M et al. Ann Rheum Dis 2005;64:34-7
Technic of reporting L.R.+DAS28-CRP-AUC 0.40
% responders (ACR20)) 1.27
% good condition (DAS < 3.2) 1.77
Time to better (ACR20) condition 1.31
Time to good (DAS < 3.2) condition 1.70
Time to sustained better (ACR20) condition 1.65
Time to sustained good (DAS < 3.2) condition 3.09
Durability good condition (unweighted Con Rew) 1.70
Status versus Changes: Feeling Good versus Feeling Better
Conclusions (1/2)
1. Evaluation of binary variables (% success) is more clinically meaningful than evaluation of continuous variables (mean changes).
2. Evaluation of status is more clinically meaningful than evaluation of changes.
3. Time to success and sustainability of the success are important points to consider.