Carefully calculated haplotype frequency sets are used in conjunction with probabilistic matching algorithms. They enable the calculation of match probabilities (shown as percentages) across donor phenotypes as well as individual loci when a search is performed in WMDA’s Search & Match Service.

With the last release of our the Search & Match Service, the WMDA has maintained a similar haplotype frequency set configuration as was used for Optimatch (Search & Match v1). In most cases the ION of the donor/cord blood unit will determine which haplotype frequency set is used.

To provide a more up-to-date representation of the donor pools worldwide, the haplotype frequency set calculations have been performed using the latest data in the WMDA Donor and CBU database. Calculations were performed using the open source algorithm Haplo-o-Mat (https://github.com/DKMS/Hapl-o-Mat and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450239/) and applying it to high resolution donor typing results received from listing organisations to extrapolate the possible haplotypes of the region or organisation. Thus, an organisation or geographical region must meet a minimum threshold of both quantity and quality HLA typed records  to build usable and valuable frequencies. For cord blood units, we will use the same sets that were determined for the donor populations.

The inclusion criteria aims to balance the high number of donors, the quality of the HLA types and the complexity of the haplotype frequency estimation.

5-Locus haplotype frequency estimation was performed on all organisations/populations with at least 10 000 donors typed for HLA-A, -B, -C, -DRB1 and -DQB1 where ambiguity was low enough to be useful. Organisations in the same country that recruit from within the same population are usually combined, e.g. AT-ABMDR (ION-2614, Austrian Bone Marrow Donors) and AT-GFL (ION-4961, Verein Geben für Leben) but not for US-NMDP (general US population) and US-GOL (predominantly Ashkenazi Jews). 

A global frequency set was also calculated and will  be used for all patients and donors that, for some reason, do not match a typical haplotype frequency set. For example, when a registry is new and has not yet been assigned to an appropriate existing haplotype frequency set or when the from this registry deviate substantially enough from any typical haplotype frequency set that it does not make sense to assign them to an existing one. The number of this frequency set is 999. Information about which haplotype frequency set is applied to a donor search is provided in the search results API endpoint. 

Below, you can find information on how the haplotype frequency sets are assigned to the donors and cord blood units. The search service first determines if both registry ION and ethnicity of the donor or cord blood unit provided. Registry ION is then used to look up the country/region that the donor or cord blood unit belongs to. If yes, then it will check if an ethnicity specific set for this registry is assigned. If the donor, for example, is coming from USA and has ethnicity HISA, then we do not have a specific set available. However, there is a more broad Hispanic haplotype frequency set available (USA-HI) and will be used in this scenario.

If there is no ethnicity available for the donor or no ethnicity specific haplotype frequency set exists for that country, the system will check if a country specific haplotype frequency set is available or if the country is part of one of the regional haplotype frequency sets.

If no country specific haplotype frequency set is available, the Search & Match Service will use the global consensus haplotype frequency set.

In the table below, you can find the haplotype frequency set numbers and which countries/organisations were included as well as the total sample size. In the last part from the table we included regional sets, some country/ethnicity specific sets and the global consensus set.

The regional sets are defined as follows:

East Asia (eas): CN (CN+CN1), HK, TW, JP (Set number: 32)

Eastern Europe (eeu):AT (A+A2), CZ (CS+CS2), CY (CY+CY2), GR2, PL (PL3+PL5+PL6), TR (TRAN+TRIS+TRKK), BG, HU, HR, LT, MK, RU (R2+R4), RO, RS, SK, SI (Set number: 33)

South America (sam): AR, BR, UY (Set number: 34)

In order for WMDA to perform these calculations on behalf of member organisations, it is important for organisations to submit donor ethnicity data and high resolution typing when available. This greatly improves the haplotype frequency sets and allows for individual donor match grades to be more accurate. 

NOTE: None of the Japanese and Korean donors have been typed for DQB1. This means that no Japanese or Korean donors were included in the calculations for set #32. Therefore, the haplotype frequency set applied to Japanese and Korean donors is likely to be biased against Japanese and Korean . We have kindly received a self-generated haplotype frequency set from the Japanese registry and are working on integrating it in the updated Search & Match Service. Whether to apply the provided Japanese haplotype frequency set or to apply set #32 is still under investigation. 

NOTE: in some cases, a country’s donors may be used in a national haplotype frequency set as well as a regional one. For example, Austrian donors are used in their own set (#2) as well as the Eastern Europe regional set (#33). When calculating match probabilities, the most specific set is always used. So for donors from Austrian Bone Marrow Donor Registry or Verein Geben für Leben set #2 is used, but for Slovakian donors there were not enough donors typed at high resolution to calculate their own set and so the regional set is assigned (#33). 

There are also countries or donors with a specific ethnic background in a country for which there was no specific haplotype frequency set in Optimas, but for which there are now enough donors for their own haplotype frequency set and/or their haplotype. We are currently investigating whether it would provide benefit to host these separately. These include: 

• IN-DATRI: Since DATRI is recruiting in a specific region of India, its haplotype frequencies may be significantly different from the haplotype frequencies found throughout the greater India (set #19).
• ZA: There are enough donors from South Africa typed at high resolution to merit its own set. Considering the unique heritage of South African donors, having frequency sets per ethnic group would be especially beneficial.

You can request that your donors be returned to the global consensus haplotype frequency set or to a regional set. Your request should include the reasons why you believe that another set is more applicable for your donors. Additionally, if your organisation has a frequency set available that you would like to see utilized for the donors of your organisation, we can implement it as well. In this case, your request should include at least a description about your population, the sample size, inclusion and exclusion criteria, calculation method, and the reasons why your haplotype frequency set would be better than the current set applied by WMDA. Both requests will be reviewed by the WMDA Bioinformatics & Innovation Working Group. Please send requests to support@wmda.info.