Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity

Matthias Haimel, Julia Pazmandi, Raúl Jiménez Heredia, Jasmin Dmytrus, Sevgi Köstel Bal, Samaneh Zoghi, Paul van Daele, Tracy A. Briggs, Carine Wouters, Brigitte Bader-Meunier, Florence A. Aeschlimann, Roberta Caorsi, Despina Eleftheriou, Esther Hoppenreijs, Elisabeth Salzer, Shahrzad Bakhtiar, Beata Derfalvi, Francesco Saettini, Maaike A.A. Kusters, Reem ElfekyJohannes Trück, Jacques G. Rivière, Mirjam van der Burg, Marco Gattorno, Markus G. Seidel, Siobhan Burns, Klaus Warnatz, Fabian Hauck, Paul Brogan, Kimberly C. Gilmour, Catharina Schuetz, Anna Simon, Christoph Bock, Sophie Hambleton, Esther de Vries, Peter N. Robinson, Marielle van Gijn, Kaan Boztug*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
3 Downloads (Pure)


Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies–defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.

Original languageEnglish
Pages (from-to)369-378
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Issue number1
Early online date11 May 2021
Publication statusPublished - Jan 2022


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