enhancement of meld w. ray kim, md mayo clinic college of medicine rochester, mn plummer building,...
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Enhancement of MELD
W. Ray Kim, MDMayo Clinic College of
Medicine Rochester, MN
Plummer Building, Rochester, MN
Agenda
• How to make MELD better
%As an indicator of pretransplant mortality• Add more variable(s): MELDNa• Optimize model: Refit MELD
%As an indicator of posttransplant outcome• Limitations
115 120 125 130 135 140 145
0.5
1.0
5.0
10.0R
isk
of
3-M
onth
M
ort
alit
y
(aft
er
ad
just
ing f
or
MELD
)
Na (mEq/L)
Serum Sodium and Mortality
Kim NEJM 2008;1018
UNOS Registrants, 2005N=6769
MELDNa: Incorporating Na to MELD
6 10 15 20 25 30 35 40
125
130
135
140
MELD
Na (
mEq
/L)
MELDNa = MELD - Na - 0.025*MELD*(140-Na) + 140
Kim NEJM 2008;1018
Validation: MELDNa vs MELD
<20 20-29 30+ <20 20-29 30+ MELD
Ob
serv
ed
/Exp
ecte
d
Based on MELD Based on MELDNa
Kim NEJM 2008;1018
Refitting CoefficientsMethods• Waitlist data obtained from OPTN from 2005-2008:
%Model derivation set (05-06): n=14,214
%Model validation set (07-08): n=13,945 • All adult, primary LTx candidates with end stage
liver disease included (HCC and status 1 excluded) • The proportional hazards regression analysis
predicting mortality within 90 days of listing
%Define lower and upper bounds
%Optimize coefficients
%Bilirubin, Creatinine, INR, and Na
Bilirubin
Bilirubin
Rela
tive R
isk
0.1 0.5 1.0 5.0 50.0
0.0
50.5
05.0
0
Bilirubin and Relative Risk of Death at 90 Days Adjusted for creatinine and INR
05-06 data
0.1
1.0
1
0.0
Bilirubin
Bilirubin
Rela
tive R
isk
0.1 0.5 1.0 5.0 50.0
0.0
50.5
05.0
0
splineMELD
Bilirubin and Relative Risk of Death at 90 Days Adjusted for creatinine and INR
05-06 data
LB=1.0
Current MELD
0.1
1.0
1
0.0
Bilirubin
Bilirubin
Rela
tive R
isk
0.1 0.5 1.0 5.0 50.0
0.0
50.5
05.0
0
splineRefit
Bilirubin and Relative Risk of Death at 90 Days Adjusted for creatinine and INR
05-06 data
LB=1.0
Refit
0.1
1.0
1
0.0
Creatinine
Creatinine
Rela
tive
Ris
k
0.1 0.5 1.0 5.0 10.0
0.5
1.0
5.0
10.
0
Creatinine and Relative Risk of Death at 90 Days Adjusted for bilirubin and INR
05-06 data
Creatinine
Creatinine
Rel
ativ
e R
isk
0.1 0.5 1.0 5.0 10.0
0.5
1.0
5.0
10.0
splineMELD
Creatinine and Relative Risk of Death at 90 Days Adjusted for bilirubin and INR
05-06 data
UB=4.0LB=1.0
Current MELD
Creatinine
Creatinine
Rel
ativ
e R
isk
0.1 0.5 1.0 5.0 10.0
0.5
1.0
5.0
10.0
splineRefit
Creatinine and Relative Risk of Death at 90 Days Adjusted for bilirubin and INR
05-06 data
LB=0.8 UB=3.0
Refit
INR
INR
Rela
tive R
isk
1 5 10
0.0
50.5
05.0
0
INR and Relative Risk of Death at 90 Days Adjusted for bilirubin and creatinine
05-06 data
0.1
1
.0
10
.0
INR
INR
Rel
ativ
e R
isk
1 5 10
0.05
0.50
5.00
splineMELD
INR and Relative Risk of Death at 90 Days Adjusted for bilirubin and creatinine
05-06 data
LB=1.0
Current MELD
0.1
1
.0
10
.0
INR
INR
Rel
ativ
e R
isk
1 5 10
0.05
0.50
5.00
splineRefit
INR and Relative Risk of Death at 90 Days Adjusted for bilirubin and creatinine
05-06 data
Refit
UB=3.0LB=1.0
0.1
1
.0
10
.0
Sodium
Na
Rela
tive R
isk
120 130 140 150 160
0.5
1.0
5.0
10.
0
Na and Relative Risk of Death at 90 Days Adjusted for bilirubin, creatinine and INR
05-06 data
Sodium
Na
Rela
tive R
isk
120 130 140 150 160
0.5
1.0
5.0
10.
0
splineRefit
Na and Relative Risk of Death at 90 Days Adjusted for bilirubin, creatinine and INR
05-06 data
Refit
LB=125 UB=140
Validation: Bilirubin
Bilirubin
Rela
tive R
isk
0.05 0.50 5.00 50.00
0.0
10.1
01.0
010.0
0
splineMELDSRTRRefit
Bilirubin and Relative Risk of Death at 90 Days Adjusted for creatinine and INR
07-08 data
*
*Sharma et al. Gastro. 2008;1575
Validation: Creatinine
Creatinine
Rela
tive R
isk
0.1 0.5 1.0 5.0 10.0
0.5
1.0
5.0
10.0
splineMELDSRTRRefit
Creatinine and Relative Risk of Death at 90 Days Adjusted for bilirubin and INR
07-08 data
*Sharma et al. Gastro. 2008;1575
*
Validation: INR
INR
Rela
tive R
isk
1 5 10
0.1
0.5
5.0
splineMELDSRTRRefit
INR and Relative Risk of Death at 90 Days Adjusted for bilirubin and creatinine
07-08 data
*Sharma et al. Gastro. 2008;1575
*1.0
10.0
Validation: MELD
MELD
Rela
tive R
isk
0 20 40 60
0.0
10.1
01.0
010.0
0
Survival at 90 Days
2007-2008 UNOS Data
07-08 data
LB (6) and UB (40) ignored for comparison purpose
Validation: SRTR MELD
SRTR
Rela
tive R
isk
2 4 6 8 10
0.1
1.0
10.0
100.0
Survival at 90 Days
2007-2008 UNOS Data
07-08 data
Validation: Refit MELD(Na)
Refit MELD Na
Rela
tive R
isk
0 2 4 6 8
0.1
1.0
10.0
100.0
Survival at 90 Days
2007-2008 UNOS Data
07-08 data
The Bottom Line
Validation Set
(2007-2008)Model Chi-Square Concordance (SE)
MELD 2263 0.8653 (0.0062)
SRTR MELD 2055 (-8) 0.8581 (0.0063)
MELDNa 2370 (+7) 0.8758 (0.0059)
Refit MELDNa 2374 (+11) 0.8768 (0.0058)
‘Kitchen Sink’ ≠ Crystal Ball‘Unsupervised’ incorporation of all potentially relevant
variables
0.8768 0.8823 0.8879
0.7
0.8
0.9
1
Refit MELDNa + Benefit Variables* Kitchen Sink**
* includes: refit MELDNa, age, BMI, albumin, HCV, diabetes, prior malignancies** includes refit MELDNa, age, sex, race, albumin, HCV, HBV, diabetes, prior malignancies, life support, encephalopathy, ascites, previous abdominal surgery, portal vein thrombosis
C-s
tati
sti
cs
MELD and Resource Utilization
1.5
2.53.0
4.0
6.1
0
1
2
3
4
5
6
7
<10 10-19 20-29 30-39 >40
0
5
10
15
20
25
30
35
<10 10-19 20-29 30-39 >40
FloorICU
pRBC LOS
1518
26
29
25
Kim ATC. 2004
Transplant Benefit
0%
20%
40%
60%
80%
100%
1 2 3 4 5 6 7 8 9 10
Survivalw/o LTx
Survival after LTx
10.3 14.7 16.8 18.5 20.5 22.5 25.1 28.4 32.7 38.7
90 D
ays S
urv
ival
C-statistics 0.57 0.88
Refit MELDNa Deciles
Mean MELD
Conclusions• Ways to improve prediction of waitlist mortality
%Add more variable: MELD Na• Represents a meaningful improvement • Big change in mortality in a subgroup of
patients%Optimize model coeffcients: Refit MELDNa
• New upper and lower bounds:• Creatinine: 0.8-3.0• INR: 1.0-3.0
%Limit to predictability• MELD and post-transplant outcome
%Statistically significant impact on survival and resource utilization
%Limited accuracy