Calling for Diversity: Improving Transfusion Safety Through High-Throughput Blood Group Microarray Genotyping

Blood transfusions, conducted between donors compatible in their red blood cell (RBC) antigens, play a life-saving role in transfusion medicine. Genetic differences at blood group loci between ethnicities result in diversity and altered frequency of RBC antigens that need to be considered in blood transfusion. Consequently, comprehensive, and accurate blood group antigen typing is especially relevant for inter-ethnic blood transfusions and for minorities underrepresented in the donor population. Blood group microarray genotyping is a cost-efficient and scalable method for comprehensive blood group typing. Previously, however, microarray typing has been challenging for the clinically important blood group systems Rh and MNS, as these feature highly paralogous genomic loci leading to mixed signals. We here present an approach for accurately typing blood group systems, including Rh and MNS variations, that we benchmarked in an ethnically diverse cohort. We tested its performance using gold-standard, diagnostic-grade MALDI-TOF data from 1,052-samples, including 334 CEPH diversity samples and applied the approach to 4,999 samples of a COVID-19 genetics study. Overall, we obtained a 99.95% benchmarking concordance and 99.65% call rate. In summary, we provide a highly accurate and cost-efficient high-throughput genotyping method for comprehensive blood group analysis that is also suitable for ethnically diverse sample sets. ### Competing Interest Statement C.G. acts as a consultant to Inno-Train GmbH, Kronberg im Taunus, Germany, a provider of genotyping kits for molecular blood group diagnostics since 1998. CG holds the European and US patents P3545102 and US20190316189 on the Determination of the genotype underlying the S-s-U- phenotype of the MNSs blood group system. The other authors declare no competing financial interests. ### Funding Statement The study was partially funded by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197). The IKMB received infrastructure support from the DFG Excellence Cluster Precision Medicine in Chronic Inflammation (Exc2167), the European Union s Horizon 2020 research and innovation program European Advanced infraStructure for Innovative Genomics, EASI-Genomics [824110], and the German Research Foundation (DFG) Research Infrastructure as part of the Next Generation Sequencing Competence Network, Competence Center for Genomic Analysis (CCGA) Kiel [423957469]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University Medical Center Schleswig Holstein Institutional Review Board of the Medical Faculty of Kiel University, Kiel Germany I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The raw genotyping data of the HGDP-CEPH panel are available via the associated database of the Fondation Jean Dausset ([www.cephb.fr][1]). All microarray and MALDI-TOF typing results are available as Supplementary Data via medrxiv Online. The data of the German cohort are available upon request from P2N biobank. Access token: P2N_859BH; . P2N is a controlled-access human data repository subject to European data protection laws. Therefore, data access is subject to an application, ethics approval by the applicant s ethics board and a data access agreement. [1]: http://www.cephb.fr