Concerns with the use of imputation to assign HLA allele-level typing in research predicting transplant outcomes

Incomplete information on HLA allele typing is a persistent problem when analyzing the role of Human Leukocyte Antigen (HLA) in transplantation. To refine the predictions possible with partial knowledge of HLA typing, some researchers use HaploStats statistics on the frequencies of haplotypes within specified ethnic/national populations to impute complete HLA allele typing. We evaluated methods that use imputation to predict patient outcomes after organ transplantation, with focus on prediction of graft survival conditional on typing information of the donor and recipient. Logical arguments show that imputation yields no predictive power when predictions are conditioned on all observed HLA typing data. Computational experiments indicate that imputation does not have predictive power when applied to risk-assessment models that make predictions conditional on only part of the observable HLA data. We therefore caution against reliance on imputation to overcome incomplete measurement. We encourage high-resolution typing of HLA antigens to improve prediction of transplant outcomes and matching of donors with recipients. Similar considerations should likely apply in other clinical settings. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No external funding was received. ### 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: This study was reviewed and exempted from approval by the Northwestern University Institutional Review Board. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The standard analysis files from the SRTR are restricted. Haplostats data is freely available using their online tool. The authors can provide code that was used to perform analysis and scrape Haplostats. To fully replicate results of this paper, researchers need to obtain standard analysis files directly from the SRTR. * HLA : Human Leukocyte Antigen KDPI : Kidney Donor Profile Index OPTN : Organ Procurement and Transplantation Network RMI : Random Multiple Imputation SRTR : Scientific Registry of Transplant Recipients