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Donor Registries

Pierre-Antoine Gourraud, Phillipe Lamiraux,

Nabil El-Kadhi, Colette Raffoux, and

Anne Cambon-Thomsen

ABSTRACT: Human leukocyte antigen (HLA) matching remains a key issue in the outcome of transplantation.

In hematopoietic stem cell transplantation with unrelated

donors, the matching for compatible donors is based on

the HLA phenotype information. In familial transplantation, the matching is achieved at the haplotype level

because donor and recipient share the block-transmitted

major histocompatibility complex region. We present a

statistical method based on the HLA haplotype inference

to refine the HLA information available in an unrelated

situation. We implement a systematic statistical inference

of the haplotype combinations at the individual level. It

computes the most likely haplotype pair given the phenotype and its probability. The method is validated on

301 phase-known phenotypes from CEPH families (Centre dEtude du Polymorphisme Humain). The method is

further applied to 85,933 HLA-A B DR typed unrelated

ABBREVIATIONS

BMD bone marrow donor

CEPH Centre dEtude du Polymorphisme Human

HLA human leukocyte antigen

INTRODUCTION

Allogeneic hematopoietic stem cell (HSC) transplantation is now a well-established curative therapy for an

increasing number of hematologic diseases [13]. The

A.C.-T.), Laboratoire Epitech de Recherche en Informatique Appliquee, Le

Kremlin Bictre, France (P.L., N.E.-K.), and FGM France Greffe de

Molle, French Registry of Hematopoetic cells Donors, Paris, France (C.R.).

Address reprint requests to: Pierre-Antoine Gourraud, INSERM Unit

558, Faculty of Medicine, 37 alles Jules Guesde, F-31000, Toulouse,

France; E-mail: gourraud@cict.fr.

Supported by EFG (Etablissement Franais des Greffes) Grant 2003,

EU contract MADO No: QLG7-CT-2001-00065.

Received December 10, 2004; revised January 3, 2005; accepted January

11, 2005.

Human Immunology 66, 563570 (2005)

American Society for Histocompatibility and Immunogenetics, 2005

Published by Elsevier Inc.

cells donors (France Greffe de Molle). The average value

of prediction probability is 0.761 (SD 0.199) ranging

from 0.26 to 1. Correlations between phenotype characteristics and predictions are also given. Homozygosity

(OR 2.08; [2.022.14] p 103) and linkage disequilibrium (p 103) are the major factors influencing the

quality of prediction. Limits and relevance of the method

are related to limits of haplotype estimation. Relevance

of the method is discussed in the context of HLA

matching refinement. Human Immunology 66, 563570

(2005). American Society for Histocompatibility and

Immunogenetics, 2005. Published by Elsevier Inc.

KEYWORDS: Donor registry; HLA haplotypes; population immunogenetics; statistical application; transplantation

HSC

OR

odds ratio

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

worldwide (http://www.bmdw.org) and the World Marrow Donor Association (http://www.worldmarrow.org/).

Nevertheless, the amount of HLA information taken

into account is different. Indeed, through typing the

patients relatives, the actual level of HLA information

used in familial HSC transplantation is the HLA haplotypes: matching is thus for two haplotypes (genoidentical situation) or only one (semi haplo-identical

situation) segregating in the family. In contrast, in

unrelated situations, the haplotype information is

known in the patient but not in the donor: that is,

there is an asymmetry in the information available.

This is usually solved by taking into account the most

minimally shared information; namely, the phenotypic

one.

The large content of the BMD registries enables the

estimate of HLA frequencies in a given population

[6 10]. The HLA population genetics data have always

been a relevant field to apply maximum likelihood

estimation of haplotype frequencies [1113]. Because

of the structure of the major histocompatibility complex region, such a method has successfully overcome

the lack of phase information at an individual level to

produce haplotype frequencies in populations. Besides

their interest from the population point of view, we

investigate here their possible use for the selection of

unrelated donors from BMD registries in individual

cases. The aim is to study how much population frequency information can be used to upgrade the donor

information taken into account for the individual decision at haplotype level rather than downgrading the

patient one at phenotype level. Knowing the genetic

background of donors throughout the registries, we

implemented a systematic statistical inference of haplotype pairs at the individual level. It computes the

most likely haplotype pair given the phenotype and

haplotype frequency information in the donors population as additional information. Incomplete phenotype

and use of HLA nomenclature is allowed.

Genetic properties influencing the accuracy of the

prediction are discussed and may be of interest in genetic

epidemiology as an example of individual haplotype inference procedure.

As reminded in the following sections, a diploid three

contiguous locus phenotype can result in a maximum

of four distinct phase configurations on the chromosomes.

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

number of possible pairs of haplotypes is n KHr1,

where the number of heterozygous loci is HR. There is

only one possible pair if only one locus is heterozygous.

The proposed algorithm deals with this issue.

Algorithm

Given haplotype frequencies, the algorithm computes

the likelihood for each possible phase. Then, it selects the

one with the maximum value:

HLA Phenotype

Locus 1-locus 2-locus

A-B-C, a-b-c L1 2 fABC fabc

A-b-C, a-B-c L3 2 fAbC faBc

A-b-c, a-B-C L4 2 fAbc faBC

likelihood of such (unambiguous) pair is the squared

value of the haplotype frequency estimation.

The probability p of the most likely pair of haplotypes

is:

P

max(Li, i n * i I)

I

i1

(1)

Li

likely haplotype pair; i is a natural integer used to

enumerate the different haplotype pairs, Li is the likelihood of haplotype pair I as defined previously, given

haplotype frequencies and Hardy-Weinberg equilibrium; and I is the overall number of possible haplotype

pairs indexed by i.

The method ability to find the most likely haplotype

pair is given by mean median (measure of central

tendency) and percentiles (a value on a scale of 100 that

indicates the percentage of the distribution of the phase

prediction value that is equal to or below it) of the

distribution of P probability defined in Equation 1 over

the considered sample.

Several alternative estimations can be provided:

those are specified, their handling is implemented in

the algorithm. For example, if A9 must be solved

considering A23 and A24 as possible alleles, the

algorithm can produce the corresponding possible

pairs and compute the corresponding likelihood. An

example is given following in the event that DR3

must be solved considering DR17 and DR18 as possible alleles:

HLA Phenotype

Locus A-Locus B-Locus DR

(1, 2)-(8, 44)-(4, 3)

HLA-DR 3 HLA-DR 17 OR 18

1-8-18, 2-44-4

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.

565

Centre dEtude du Polymorphisme Human (CEPH)

families have been used to apply the algorithm on

phase-known data (data available on request). HLA-A,

-B, -DR haplotypes were deduced from the familial

study of HLA segregation [14]: 301 different pairs of

HLA-A, -B, -DR haplotypes were obtained from 39

families. The algorithm for prediction deals with each

phenotype. The outcome is compared with the actual

phase as defined by the study of segregation. The 2

test assesses the statistical significance of the predicted

accuracy of the method.

Application on Phase-Unknown Population Data

Potential donors from the French BMD Registry typed

for HLA-AB and -DRB1 were used (N 85,933). The

haplotype estimation is based on the likelihood methods implemented within an expectation maximization

algorithm according to the previously implemented

procedures [6, 7]. As an approximation, all individuals

with only one allele at a given locus were analyzed as

homozygous at this locus. The description of the population can be found on the annual report of the French

Registry (http://www.fgm.fr). The debate on the use of

the BMD Registry to infer HLA haplotype frequencies

has been largely discussed, as has the potential bias

(such as selection on HLA-DR typing) [6 10].

Prediction statistics distribution and properties are

presented on the results obtained from the BMDs dataset. A prediction probability is given to each most likely

haplotype pair assigned in the context of the search for

unrelated hematopoietic stem cell donor.

The likelihood of each haplotype pair is based on the

phenotype of the individual and on the population haplotype frequencies. A priori, each haplotype pair has the

same chances to occur, thus defining a minimal prediction value. For example, in a phenotype with three

heterozygous loci, four pairs of haplotypes are possible.

In this case, the minimal prediction value is 25%. This

minimal value would be the one obtained in absence of

gametic disequilibrium.

The detailed description of the outcome of this prediction is given in the set of the HLA-ABDR phenotypes

of French BMD Registry. The influence of several factors

has been evaluated. Key factors that are correlated with

the quality of the prediction outcome were quantified by

odds ratio (OR) and tested using the 2 test.

RESULTS

Of 301 phase-known phenotypes from CEPH families,

the observed number of correct predictions is 69.4%

(n 209/301). According to the prediction probabil-

566

percentile of haplotype inference

probability for HLA phenotype for 85,933

French unrelated bone marrow donors

HLA-A, -B, -DR phenotypes (bottom) and

HLA-A HLA-B phenotypes (top)

Phenotype A, B

Percentile (%)

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

Last column reports 95% confidence intervals (CIs) of the percentiles

estimated.

predict an individual haplotype pair is expected to be

76.64% (standard deviation 20.4%). The observed

number of correct predictions is not significantly different from the expected number (2 test, p 0.17).

Among the 85,933 phenotypes typed for HLA-A, -B,

-DR, the average value of HLA-ABDR haplotype pairs

prediction probability is 0.761 (standard deviation

19.9%), ranging from 0.26 to 1. Table 1 shows the

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.

their 10th, 25th, 50th, 75th, and 90th percentiles for

HLA-ABDR haplotype pairs and HLA-AB haplotype

pairs prediction. The distribution of the prediction probability in HLA-A, -B, -DR phenotypes and HLA-A, -B

phenotypes is given in Figure 1.

Many huge differences do exist between phenotypes,

suggesting the interplay of various parameters: allele and

haplotype frequency, homozygosity, and linkage

disequilibrium.

To clarify the different factors influencing the outcome of the prediction, examples are given in Table 2.

This table is divided into four parts according to the

prediction reliability. Individuals with at least two loci

considered as homozygous represent two thirds (4760/

6223) of the predicted haplotype pairs given as nonambiguous (p1) (Table 2, Part 1). The remaining ones

(1463/6223) correspond to different situations as

shown in Table 2, part 2. They include the associations

of a frequent haplotype and a rarer one, or two quite

rare haplotypes in a strong linkage disequilibrium.

This also applied to predictions close to 1, including

some phenotypes made of two frequent haplotypes

(Table 2, Part 3).

As expected, the level of prediction is low prediction

when phenotypes include several frequent alleles in low

linkage disequilibrium. Examples are given in Table 2,

part 4.

A few factors seem to be the major ones influencing

the likelihood of the prediction: the degree of homozygosity, the frequency of the alleles, the frequency of

haplotypes predicted, and the linkage disequilibrium

(the nonrandom association of alleles at two physically

linked loci). Their consequences have been quantified by

OR and underscore the following facts:

567

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

Haplotype 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

Haplotype 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

Haplotype 1

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)

568

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%.

associated with an increased prediction probability

(OR 2.08; [2.022.14] p 10.3).

2. The presence of the most frequent HLA alleles in the

phenotype is not correlated with a high prediction

value (p 0.05). In absence of a significant linkage

disequilibrium, the allele frequency does not play a

key role in the prediction outcome (data not shown).

3. Linkage disequilibrium also increases the prediction

probability. Having at least a standardized pair-wise

linkage disequilibrium |D'LociXY| 0.5 is positively correlated with higher prediction probability

(|D'HLA*AHLA*B|; OR 1.74 [1.69 1.79] p 10.3)

(|D'HLA*BHLA*DR|; OR 1.12 [1.09 1.16] p

10.3). Interestingly, further analysis (not shown) indicates that the positive linkage disequilibrium measures (association) are correlated with increased phase

prediction probability (p 10.3), whereas negative

linkage disequilibrium measures (repulsion) are correlated with decreased phase prediction probability (p

10.3). Moreover, the positive linkage disequilibrium

between three loci is strongly associated with higher

prediction probability (D'HLA*AHLA*BHLA*D 0.01;

OR 6.7 [6.46 6.95] p 10.3).

Homozygosity and positive linkage disequilibrium

are the major factors influencing the prediction quality.

DISCUSSION

In this article, we addressed the possibility of predicting

haplotype phase from individual HLA phenotypes. We

described the outcome of the proposed method on 301

phase-known individuals of the CEPH panel and on

85,933 HLA-ABDR phenotypes of the French BMD

Registry. Key factors correlated with the quality of the

prediction outcome were homozygosity and the linkage

disequilibrium, which clearly increase the prediction

probability. This study on individual phase inference is

information available in familial situations can be

reached by statistical method in an unrelated situation.

The haplotype prediction method also contributes to

show that individual haplotype prediction could be of

practical use. The method is a way to incorporate the

current knowledge of the HLA region linkage disequilibrium through the registries in the interpretation of

their phenotype. Other studies focusing on haplotype

inference in HLA region deal preferentially with some

association studies than transplantation genetics [15,

16]. In other genetic regions, several studies have demonstrated the power of haplotype prediction. Examples

are available in Xu et al. [17] for five single nucleotide

polymorphism (SNP)s in N-acetyl transferase 2 gene

(NAT2, 8p22) and for five SNPs on the X chromosome

(Xp11.4) or in Orzack et al. for nine apolipoprotein E

sites (APOE 19q13.22) [18]. The relevance of such an

approach is always discussed regarding the phase predicted rather than the prediction value. Thus the relevance of the haplotype prediction methods must be assessed depending on the kind of markers used and on the

genomic region considered. Validation of the predicted

haplotype phase probability in itself is difficult in practice. For each phenotype, it would require a significant

sample of phase-known HLA data from unrelated

individuals.

The haplotype approach is powerful because it reduces the number of theoretic possible phenotypes

analyzed.

The method assumes that the haplotype frequency

estimations and the phenotypes under analysis are drawn

from the same population. The individual HLA data

from CEPH families and the potential BMD phenotype

data were recruited within the French population. The

French BMD Registry provides haplotype frequency estimations. The fact that the registry haplotype frequencies are used as approximations of the source population

Registry, the DR-typing bias has been reduced in recent

years. Nevertheless, at the individual level, haplotype

phase inference is limited by the origins of the donors.

The phase prediction for individuals in non-Caucasian

CEPH families (Amish and Venezuelan, for example)

provides evidence that applications should be restricted

to the population used for the haplotype frequency estimation. Thus different population haplotype frequency

estimation should be used in cases of different genetic

background. In the context of HLA and transplantation,

haplotype analysis has been mainly used at the population level, especially to model the likelihood to find a

donor [20, 21]. However, the results presented here show

that an application at the individual level may also help

to assess the degree of haplotype matching for unrelated

transplantation.

No matter the sample size, no matter the number of

haplotype frequency estimations used to compute the

phase prediction, the method is limited: no prediction

probability can be lower than 0.25 (threshold for random

attribution of phase in three heterozygous loci phenotypes). It is possible that none of the haplotypes required

to explain the phenotypes were estimated in the reference

sample. In this case, it is not possible to compute prediction probability. Even if confidence intervals may be

computed by bootstrap methods of haplotype frequency

estimation, sampling errors on very rare haplotypes remains the main source of variability of the estimation [22].

Haplotype pair predictions may be routinely given to

clinicians by the prediction tools described here. They

have been implemented by France Greffe de Moelle. On

request, haplotype phase prediction is performed using

the latest estimation of HLA-ABDR haplotype frequencies in the source population. While sorting to indicate

the predicted pair of haplotypes, Registry data remain

unchanged. In some cases, the user may explore the

likelihood of all possible haplotype pairs.

By the implementation of simple statistics, the

method presented provides more HLA information to

help decide for soliciting donors. Such a tool implemented in the BMD Registries may be of practical

interest in several aspects. It would evaluate the chances

for a phenotype to match a given haplotype. The results

presented here suggest that most (about 76%) of the

HLA-A, -B, -DR phenotype matching individuals are

matched at the haplotype level in the French BMD

Registry. Some of them are compatible with the phenotype level only. It confirms from the statistical point of

view previous finding that show that ancestral haplotypes (strong linkage or positive linkage disequilibrium)

increased survival in unrelated transplantation [23, 24].

A similar study could be interesting using HLA haplotype frequencies at higher resolution level to investi-

569

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

France Greffe de Moelle staff and the bioinformatics platform

of Genopole Toulouse Midi-Pyrnes.

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