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INTRODUCTION
Allogeneic hematopoietic stem cell (HSC) transplantation is now a well-established curative therapy for an
increasing number of hematologic diseases [13]. The
HSC
OR
role of human leukocyte antigen (HLA) matching between donor and recipient has been studied by many
groups over the past years, but its optimal level remains unclear [4, 5]. The development of molecular
typing techniques allows a refined matching and
thus contributes to reduce risk of graft immunologic
failure from host-versus-graft and graft-versus-host
allorecognition.
The best donor remains an HLA-matched relative, but
such a donor is not always available. In 70% of the cases,
a search for an unrelated HLA-matched donor is performed
among the 9.1 million bone marrow donors (BMDs) gathered in 54 stem cell donor registries from 40 countries and
0198-8859/05/$see front matter
doi:10.1016/j.humimm.2005.01.011
564
HLA Phenotype
Locus A-Locus B-Locus DR
(1, 2)-(8, 44)-(4, 3)
1-8-3, 2-44-4
Possible
1-44-3, 2-8-4
pairs of
1-8-4, 2-44-3
haplotype
1-44-4, 2-8-3
max(Li, i n * i I)
I
i1
(1)
Li
1-44-18, 2-8-4
1-8-4, 2-44-18
1-44-4, 8-2-18
1-8-17, 2-44-4
1-44-17, 2-8-4
Possible
pairs of
haplotype
1-8-4, 2-44-17
1-44-4, 2-8-18
Haplotype prediction software achieves the same computations over the set of possible phases that is deducted
from the implementation of nomenclature codes.
2. Phenotypes are sometimes incomplete. To predict the
possible haplotypes in such cases, the algorithm produces all possible haplotype pairs corresponding to
the incomplete phenotype and computes the corresponding likelihood.
During the phase prediction, a set of options manages
the implementation of the nomenclature and the replacement of missing values in the phenotype. These features
are implemented in a software named haplopred (available on request to the authors). Computations are easily
achieved on a personal computer. It is a C-written software developed with corresponding libraries to make it
usable in a flexible way to BMD registry computer
system management.
The algorithm presented requires a set of haplotype
frequencies. It has been applied to two sets of HLA
data. The first one consists of individuals with known
haplotypes from family segregation to validate the estimation of haplotype pairs predicted by statistics. The
second one consists of unrelated phase-unknown individuals from the French BMD Registry to describe the
outcome of the method.
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Value
CI (95%)
10
25
(Median) 50
75
90
0.592
0.733
0.937
0.997
1
0.5900.594
0.7300.737
0.9370.937
0.9960.997
X
Phenotype A, B, DR
Percentile (%)
Value
CI (95%)
10
25
(Median) 50
75
90
0.481
0.588
0.794
0.956
0.994
0.4790.484
0.5860.59
0.7920.797
0.9550.957
0.9930.994
FIGURE 1 Distribution of
haplotype prediction given phenotypes on 85,933 French unrelated bone marrow donors. Distribution of prediction obtained
on human leukocyte antigen
(HLA)-A HLA-B phenotypes are
given in white. Distribution of
prediction obtained on HLA-A,
HLA-B, HLA-DR phenotypes
are given in black.
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TABLE 2 Table of examples of haplotype pair prediction on 85,933 French unrelated bone marrow donors
Part 1: Phenotype with at least two homozygous loci
Haplotype 1
Frequency 1
Haplotype 2
Frequency 2
Prediction value
3-7-15
3-7-1
2-35-11
2-44-1
2-62-4
1-8-15
0,0257
0,0032
0,0032
0,0056
0,0091
0,0035
3-7-15
3-40-1
2-35-13
2-27-1
2-62-13
1-8-17
0,0257
0,0001
0,0021
0,0035
0,0046
0,0227
1
1
1
1
1
1
Frequency 1
Haplotype 2
Frequency 2
Prediction value
2-60-11
1-8-7
1-8-17
3-64-13
1-37-7
30-18-17
2-39-14
2-7-17
26-38-13
2-41-13
0,0012
0,0023
0,0227
0,0002
0,0003
0,0040
0,0004
0,0005
0,0032
0,0008
29-44-11
31-44-7
3-53-17
3-7-8
25-44-7
30-39-1
25-18-14
25-8-17
66-41-13
11-35-103
0,0026
0,0007
1,4e-5
0,0011
0,0001
4,0e-5
0,0003
0,0002
0,0003
0,0007
1
1
1
1
1
1
1
1
1
1
Frequency 1
Haplotype 2
Frequency 2
Prediction value
1-8-3
1-8-17
3-7-15
2-13-7
2-12-4
3-14-7
1-8-17
2-44-16
1-8-13
1-8-3
2-60-13
1-17-7
2-57-7
1-8-3
1-8-3
24-57-7
0,0227
0,0227
0,0257
0,0035
0,0015
0,0006
0,0227
0,0022
0,0030
0,0227
0,0046
0,0018
0,0045
0,0227
0,0227
0,0011
3-35-1
2-62-4
30-13-7
29-44-7
29-12-07
03-35-11
1-44-16
68-65-13
3-18-13
11-5-15
23-44-7
3-35-1
30-18-3
11-56-1
2-62-2
24-62-4
0,0125
0,0091
0,0044
0,0273
0,0016
0,0034
8,4e-5
0,00085
0,0005
3,5e-5
0,0082
0,0125
0,0039
0,0004
0,0002
0,0016
0,9921
0,9855
0,9938
0,9844
0,9511
0,9961
0,9985
0,9782
0,9875
0,9697
0,9649
0,9868
0,9789
0,9964
0,9566
0,9795
Frequency 1
Haplotype 2
Frequency 2
Prediction value
2-51-4
1-51-4
2-44-4
2-44-4
2-51-13
2-44-11
2-60-13
3-51-11
24-62-11
2-18-1
3-56-11
0,0039
0,0008
0,0207
0,0207
0,0058
0,0074
0,0046
0,0013
0,0018
0,0010
0,0001
24-62-13
2-44-7
24-51-1
24-60-13
28-44-11
24-27-1
3-51-4
11-35-13
32-35-1
32-39-4
24-51-13
0,0031
0,0104
0,0003
0,0003
0,0010
0,0007
0,0010
0,0022
0,0007
0,0001
0,0009
0,3468
0,3448
0,3166
0,3273
0,3339
0,3150
0,3488
0,3335
0,3253
0,3096
0,2915
(Continued)
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TABLE 2 (Continued)
Part 4: Haplotype pair prediction 35%
Haplotype 1
Frequency 1
Haplotype 2
Frequency 2
Prediction value
11-18-13
2-51-14
2-21-13
2-62-13
2-51-7
0,0002
0,0017
0,0002
0,0046
0,0028
32-44-1
3-18-10
3-40-4
3-27-4
24-49-13
0,0003
2,5e-5
0,0002
0,0007
0,0005
0,3235
0,3295
0,3314
0,3215
0,3473
Part 1 presents the prediction of the most likely haplotype pair of human leukocyte antigen (HLA)-A B DR phenotypes, which has at least two homozygous loci.
Part 2 presents the prediction of the most likely haplotype pair of HLA-A B DR phenotypes, which result is nonambiguous two homozygous loci. Part 3 presents
the prediction of the most likely haplotype pair of HLA-A B DR phenotypes for which prediction value is between 95% and 1. Finally, Part 4 presents the
prediction of the most likely haplotype pair of HLA-A B DR phenotypes, for which prediction value is below 35%.
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gate to which extent higher level of HLA-typing influences the matching at haplotype level in unrelated
situation. Handling other HLA locus or genetic markers
in the HLA region may also help to define the compatibility at haplotype level.
The findings presented here can be applied to assess
the degree of HLA matching in any kind of transplantation or when typing relatives is not possible. For example, the phase prediction probabilities assessing the
HLA-ABDR haplotype matching may indicate further
HLA-typing requirements. It can also characterize the
identity for one haplotype in unrelated situations when
only partially incompatible donors are available.
We demonstrated here that taking advantage of the
genetic structure of HLA data allows accessing more
information than expected. It has a general relevance as a
decision element used in the assessment of compatibility
in transplantation. Thoughtful statistics considerations
on immunogenetics and populations may allow the development of practical tools of clinical relevance.
ACKNOWLEDGMENT
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