HLA-A,-B,-C e DRB1 distribution in the national population– systematic

review for assessment of the adequate inventory size and heterogenic

composition of hematopoietic stem cell registries
S.M. Duarte, M.F. da Graça, J.S. Baptista

Programa Doutoral Em Segurança e Saúde Ocupacionais, FEUP, Portugal

ABSTRACT
Background: The necessity to establish a National Cord Blood bank is emphasized further by an adequate
inventory size and heterogeneity of HLA allele and haplotype distribution in the population. Due to the high
level of molecular variation of HLA alleles and halotypes, an assessment of HLA-A,-B,-C e DRB1 national
distribution need to be performed. The aim of this study is to present a systematic review of the different
approaches and methodologies used to analyze HLA-A,-B,-C e DRB1 distribution and their inference in
development an adequate inventory size and heterogenic composition of hematopoietic stem cell registries
setting up.
Methods: Following PRISMA guideline, one author performed the initial search on MetaLib database,
accessed through April-September 2013. The search strategy was based on combinations of the appropriate
key search strings. Reference lists of selected studies were also searched. Studies were screened according to
pre-defined inclusion and exclusion criteria. All eligble papers were critically appraised for assessed for
methodological quality and eligible for inclusion or segregation of each study was determined by argument
with two others reviewers. A third reviewer was consulted for disagreements.
Results: 192 studies were obtained. From those were excluded: 88 duplicates and 64 based on title, abstract
or off topic. 38 studies were assessed for eligibility. From those were excluded: 11 published before 2009 and
21 not meet quality criteria. 6 studies were included in qualitative synthesis. Data from selected studies were
extracted and summarized in evidence table.
Conclusions: All the 6 studies selected, produce multifaceted statistical data using novel statistical methods
that enable the basis for analyze HLA-A,-B,-C e DRB1 distribution and their inference in development an
adequate inventory size and heterogenic composition of hematopoietic stem cell registries setting up.

Keywords: Cord blood, HLA, geographic distribution, hematopoietic stem cell

Due to the high level of molecular variation of HLA

1 BACKGROUND
HLA class I and class II, play an important role in
immunity response and in hematopoietic stem cell
transplantation (HSCT) .
The allogenic transplantation of hemopoietic stem
cell is restricted by the necessity to identify HLA
matched donor within biological siblings or in bone
marrow voluntary donor registries or cord blood
banks for altruistic use . On the other hand, the
feasibility of identifying an HLA match donor
depends on the patient’s specific HLA alleles and
ethnicity .
Currently, more than 21 million volunteers donors
and cord blood units are registered in the Bone
Marrow Donor Worldwide (BMDW) database .
Despite that, not all patients, are able to find a
suitable donor, only 50% of patients are transplanted
using an unrelated donor .
Patients of ethnic minorities’ goups have a low
probability (1/10) of identifying a donor-matched .
alleles and halotypes , an assessment of HLA-A,-B,-
C e DRB1 national distribution need to be
performed, in order to optimized the adequate
inventory size and heterogenic composition of
hematopoietic stem cell registries.
This systematic review was commissioned to
provide a comprehensive assessment of the different
approaches and methodologies used to analyze
HLA-A,-B,-C e DRB1 distribution and their
inference in development an adequate inventory size
and heterogenic composition of hematopoietic stem
cell registries setting up.
2 METHODS
Search strategy and study selection
Following PRISMA guidelines one author (S.M.D.)
performed the initial search through April-
September 2013, using the MetaLib database. The
data were extracted from already published literature
and therefore, no institutional research ethics board
approval was needed. The search strategy was based
on of the appropriate key search strings (‘Cord blood
bank’ AND ‘Inventory size’ OR ‘Heterogenic
composition’ OR ‘Allele frequency’ OR ‘Halotype
frequency’ OR ‘Geographic distribution’ OR ‘Bone
marrow donors’ OR ‘Planning’ OR ‘HLA’.
Reference lists of selected studies were also
searched.
Inclusion and exclusion criteria
Portuguese, Spanish and English language was
eligible. No restrictions were made with respect to
gender, ethnicity, and population size and study
design. All original publications types in peer-
reviewed journals were eligible. Reviews, letters,
unpublished manuscripts, dissertations, books and
books chapters and consensus development
statements were not eligible. The search was limited
to the last eight years, but for assessment of
methodological quality, studies published from 2009
were eligible.
Data management and assessment
All studies were screened initially by author, title,
abstracts (when available), year of publication and
editor, and then more thoroughly in full text. The
studies were ranked as: (1) Article for further
assessment (2) Article excluded based on title and
abstract or without outcome of interest (3) Repeated.
Eligible for inclusion or segregation of each study
was determined by argument with the others
reviewers. A third reviewer was consulted for
disagreements.
Methodological quality
Studies meeting the inclusion criteria were critically
appraised for assessed for methodological quality.
The studies were ranked as (1) Article included in
the systematic review (2) Article exclude: did not
meet quality criteria.
3 RESULTS
Result of the search and sifting process
A flow diagram of the search and sifting process is
presented in Figure 1.
Figure 1. Flow diagram of the search and
sifting process
192 studies were obtained (Haematologica 1,
Highwire Press 134, Informaworld (Taylor and
Francis) 10, Oxford Journals 33, PlosOne 1, Science
Direct 5 and Wiley Online Library 8). From those
were excluded: 88 duplicates and 64 based on title,
abstract or off topic (2 without author´s (1 it is not
under active consideration for publication has not
been accepted for publication nor has it been
published, in full or in part)).
38 studies were assessed for eligibility. From those
were excluded: 11 published before 2009 and 21 not
meet quality criteria. 6 studies were included in
qualitative synthesis. Data from these studies were
extracted and summarized in evidence Table 1, with
the following headings: Author, year; study design;
study population n; variables examined,
approaches/methodologies; author´s
comments/conclusions and key findings relevant.
Table 1. Description of the included articles
Author, year Study design Study Variables Approches/ Author’s commments/conclusions
population examined methodologies Key findings relevant
n
Yoon JH et al Original research-Brief report 17,508 CBUs Halotypes Stage 1-Hardy-Weinberg Considering the inventory size according to the cell number of CBUs and also the
2013 Estimation of CB inventory size in containing three equilibrium (HEW) tests intermediate resolution of HLA-DRB1
Koreans with stored CBUs and HLA loci (A, B, and linkage disequilibrium Estimation based on HLA types from real patients, reflect the real situation but it is
patients who underwent allogeneic DRB1) and two- for HLA-A, -B, and –DRB1 biased for commom HLA types
hematopoietic stem cell digits HLA genotypes and Expectation-
transplantation specificities maximization (EM) for
HLA-A, -B, and –DRB1
halotypes
Stage 2- Maximum-
likelihood estimation via the
expectation maximum
algorithm for allele and
halotype frequencies
Stage 3- Bootstrap method
for computing the matching
probabilities for 4/6, 5/6 and
6/6 matching patients
Katri Haimila Original research 21.534 HLA Halotypes Bootstrap resampling for Data from CB banks is mainly at the low resolution level
2013 Comparation of HLA halotype halotypes (2910 containing three computing the matching The distribution of different halotypes is more significant to find an HLA-matched
distribution between CB units CBUs more HLA loci (A, B, probabilities for 6/6, 4/6, 5/6 donor for a patient. The recruiting policy of a bank should be designed to
banked and BM donors registry 18,624 potential DRB1) with one restriction (one maximize haplotype distribution coverage
(data not shown) BM donors) mismatch for HLA-DRB1 The tendency to a homogenous HLA haplotype distribution in banks underlines
locus the need for targeting recruitment at the poorly represented minority populations
Buhler et al Original research HLA molecular HLA -A, -B, -C, Non-parametric and Improvement of specifically adapted statistical methods and software
HLA -A, -B, -C, -DRB1 halotype fequencies obtained are very close but the
2013 Estimation of allelic and halotypic data of 20,000 -DRB1 and – resampling statistical tests to
approach used as the advantage of taking ambiguities into account, being more
frequencies HSCT donors DQB1 assess Hardy-Weinberg precise
from 9-13 equilibrium (HEW), Sugets strategies based on phenotype rather than halotypedrequencies for help
recruitment selective neutrality and refining the recuritment of donors and provide better predictions
Estimation not based on specific search of matched HLA donors for a given
centers linkage disequilibrium
patient in need of a transplant , providing long-term recommendations about the
best recruitment strategies to implement to enhance the HLA diversity in registries
Justification of the maintenance of a decentralized donor recruitment structure in
Switzerland allowing increasing the genetic diversity of the national—and hence
global—donor registry
Table 1. Description of the included articles (cont.)
Author, year Study design Study Variables Approches/ Author’s commments/conclusions
population examined methodologies Key findings relevant
n
Julia Pingel Original research DKMS German Halotypes of Expectation-maximization For populations studies, the rational parameter to be assessed would be the
2013 Estimation high-resolution HLA- Bone Marrow donors with (EM) algorithm ethnicity of a donor
A, -B,-C e –DRB1 halotype and Center from 17 parentage Dificulty in the analysis of GD due to the influenci of the different in sample size
allele frequencies different Four-locus and the resulting differences in alleles and allele frequencies observed for a certain
countries halotypes (HLA population
Samples sizes loci A, B, C and HLA halotype frequencies presented are characteristic of the respective minorities
ranging from DRB1) and five- Efficient donor recruitment should considerer age and gener of a donor. In a global
1021 to 33,083 locus halotypes picture , genetic distances of populations and optimal size of a donor registry
(HLA loci A, B, should play a role
C, DRB1 and Predictions specific to a certain population , are more accurate and thereby speed
DQB1) up the search for an unrelated donor
Demonstration how genetic differences between populations are reflected in
matching probabilities of recipient/donor pairs and how they influence the search
for unrelated donors as well as strategic donor center typings
A.H. Original research 320,000 German Loci HLA -A, - Five digit postal code Relevance of regional HLA differences for practical donor registry planning, that
can be used to diminish the problem of decreasing marginal benefit of donor
Schmidt Regional differences in HLA-A, - donors B, -C and - system for geographic
recruitment
2010 B and –DR antigen and halotype DRB1 (exons 2 partioning
frequencies and 3 for class I Hardy-Weinberg
loci, exon 2 for equilibrium (HEW) and
class II loci) halotype frequencies
calculations through the
Expectation-maximization
(EM) algorithm were carried
out with the ARLEQUIN
software package
Genetic distances combined
Cavalli-Sforza and Edwards
chord distances
A. H. Original research Unbiased data HLA -A, -B, -C The Arlequin software Relevance of high resolution matching of HLA -A, -B, -C and -DRB1 for
package was used to outcomes of hematopoietic stem cell transplantation, significant for strategic
Schmidt Estimation of allelic and halotypic set of 8,862 and -DRB1
calculate haplotype planning and resource allocation of donor centers and registries
2009 frequencies German stem typed at high frequencies via the Relevance of matching requirements on the probability to find fully matched
Estimation of the probability of cell donors resolutions Expectation-maximization donors and therefore an appropriate donor registry sizes
funding fully matched donors Eligibility (EM) algorithm and to Ongoing donor recruitment seems essential to compensate for aging
check for Hardy- of registered donors, but there is also a need for innovative
criteria: (male
Weinberg equilibrium recruitment strategies that efficiently increase the number of available
gender, age <26 (HWE) HLA phenotypes
years
 4 DISCUSSION

The study designs of the 6 studies selected, were

based on HLA-A, -B,-C, –DRB1 and DQB1
halotype and allele frequencies typed at low
resolution or high resolution. 2 studies examined
halotypes containing loci HLA -A, -B and -DRB1; 2
studies examined halotypes containing loci HLA -A,
-B, -C, and -DRB1; and 2 studies examined
halotypes containing loci HLA -A, -B, -C, -DRB1
and –DQB1. 2 studies also aimed to estimate the
probability of funding fully matched donors.
3 studies used data from cord blood units (CBUs),
and the others 3 studies used hematopoietic stem cell
transplantation (HSCT) potential donors from
recruitment centers.
The approaches/methodologies used were based on
different combinations of statistical methods. In 1
study a three-stage procedure was used: (1) Hardy-
Weinberg equilibrium (HEW) tests and linkage
disequilibrium for HLA-A, -B, and –DRB1
genotypes and Expectation-maximization (EM) for
HLA-A, -B, and –DRB1halotypes (2) Maximum-
likelihood estimation via the expectation maximum
algorithm for allele and halotype frequencies (3)-
Bootstrap method for computing the matching
probabilities; 1 study used Bootstrap resampling for
computing the matching probabilities; 1 study used
an improvement of Hardy-Weinberg equilibrium
(HEW), selective neutrality and linkage
disequilibrium; 1 study used Expectation-
maximization (EM) algorithm; 1 study used a five
digit postal code system for geographic portioning
and Hardy-Weinberg equilibrium (HEW) and
halotype frequencies calculations through the
Expectation-maximization (EM) algorithm were
carried out with the ARLEQUIN software package;
and 1 study used the Arlequin software package was
used to calculate haplotype frequencies via the
Expectation-maximization (EM) algorithm and to
check for Hardy- Weinberg equilibrium (HWE).

5 CONCLUSIONS

The aim of this study was to present a systematic

review of the different approaches and
methodologies used to analyze HLA-A,-B,-C e
DRB1 distribution. All the 6 studies selected,
produce multifaceted statistical data using novel
statistical methods that enable the basis for analyze
HLA-A,-B,-C e DRB1 distribution and their
inference in development an adequate inventory size
and heterogenic composition of hematopoietic stem
cell registries setting up.
Bibliografy