Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity - 05/01/22

Doi : 10.1016/j.jaci.2021.04.033

Matthias Haimel, PhD ^a,^b,^c,^{^{∗
These authors contributed equally to this work.}}, Julia Pazmandi, MSc ^a,^b,^c,^{^{∗
These authors contributed equally to this work.}}, Raúl Jiménez Heredia, MSc ^a,^b,^c, Jasmin Dmytrus, MSc ^a,^b,^c, Sevgi Köstel Bal, MD, PhD ^a,^b,^c, Samaneh Zoghi, PhD ^a,^b,^c, Paul van Daele, MD ^d, Tracy A. Briggs, PhD ^e,^f, Carine Wouters, MD ^g,^h, Brigitte Bader-Meunier, MD ^i,^j, Florence A. Aeschlimann, MD ^i,^j, Roberta Caorsi, MD ^k, Despina Eleftheriou, MD ^l,^m, Esther Hoppenreijs, MD ⁿ, Elisabeth Salzer, MD, PhD ^a,^b,^c,^al, Shahrzad Bakhtiar, MD ^o, Beata Derfalvi, MD ^p, Francesco Saettini, MD ^q, Maaike A.A. Kusters, MD, PhD ^l,^m, Reem Elfeky, MD ^l,^m, Johannes Trück, MD, DPhil ^r, Jacques G. Rivière, MD ^s,^t, Mirjam van der Burg, PhD ^u,^v, Marco Gattorno, MD ^k, Markus G. Seidel, MD ^w, Siobhan Burns, MD ^x, Klaus Warnatz, MD ^y,^z, Fabian Hauck, MD, PhD ^aa,^ab, Paul Brogan, MD ^l,^m, Kimberly C. Gilmour, PhD ^m, Catharina Schuetz, MD ^ac, Anna Simon, MD, PhD ^ad, Christoph Bock, PhD ^a,^c,^ae, Sophie Hambleton, PhD ^af, Esther de Vries, MD, PhD ^ag,^ah, Peter N. Robinson, MD ^ai, Marielle van Gijn, PhD ^aj,^{^{‡
These authors contributed equally to this work.},}^⁎ , Kaan Boztug, MD ^a,^b,^c,^ak,^al,^{^{‡
These authors contributed equally to this work.},}^⁎
^a Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
^b St Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
^c CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
^d Department of Clinical Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands
^e NW Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
^f Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
^g Department of Microbiology and Immunology, Immunobiology, KU Leuven, Leuven, Belgium
^h Department of Pediatrics, Division of Pediatric Rheumatology, University Hospitals Leuven, Leuven, Belgium
ⁱ Pediatric Immuno-Hematology and Rheumatology Unit, Necker Hospital for Sick Children - AP-HP, Paris, France
^j Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE), Paris, France
^k Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Istituto Giannina Gaslini, Genova, Italy
^l University College London Great Ormond Street Institute of Child Health, London, United Kingdom
^m Department of Immunology, Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust, London, United Kingdom
ⁿ Department of Paediatric Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands
^o Department for Children and Adolescents, Division for Stem Cell Transplantation, Immunology and Intensive Care Unit, Goethe University, Frankfurt, Germany
^p Department of Pediatrics, Division of Immunology, Dalhousie University/IWK Health Centre Halifax, Halifax, Nova Scotia, Canada
^q Pediatric Hematology Department, Fondazione MBBM, University of Milano Bicocca, via Pergolesi 33, Monza, Italy
^r Division of Immunology, University Children’s Hospital Zurich, Zurich, Switzerland
^s Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
^t Jeffrey Model Foundation Excellence Center, Barcelona, Spain
^u Department of Immunology, University Medical Center Rotterdam, Rotterdam, The Netherlands
^v Laboratory for Pediatric Immunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
^w Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria
^x Department of Immunology, UCL Institute of Immunity & Transplantation, Department of Immunology, Royal Free Hospital NHS Foundation Trust, London, United Kingdom
^y Division of Immunodeficiency, Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^z Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^aa Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
^ab Munich Centre for Rare Diseases (M-ZSE^LMU), University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
^ac Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
^ad Radboudumc Expertise Centre for Immunodeficiency and Autoinflammation (REIA), Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
^ae Institute of Artificial Intelligence and Decision Support, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
^af Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
^ag Tranzo, Tilburg University, Tilburg, The Netherlands
^ah Laboratory for Medical Microbiology and Immunology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands
^ai The Jackson Laboratory for Genomic Medicine, Farmington, Conn
^aj Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
^ak Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
^al St Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

^∗Corresponding author: Kaan Boztug, MD, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) and St. Anna Children’s Cancer Research Institute (CCRI), Zimmermannplatz 10, A-1090 Vienna, Austria.Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) and St. Anna Children’s Cancer Research Institute (CCRI)Zimmermannplatz 10ViennaA-1090Austria^∗∗Marielle Van Gijn, PhD, Department of Genetics, University Medical Center Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands.Department of GeneticsUniversity Medical Center GroningenAntonius Deusinglaan 1GroningenThe Netherlands9713AV

Abstract

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.

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Key words : HPO, ontology, phenotype, rare diseases, inborn errors of immunity, immunodeficiencies, disease classification, diagnostic support, patient matching, genetic analysis

Abbreviations used : ESID, HPO, IEI, IUIS, PAD

Plan

Methods

Establishment of working structure

Expansion and restructuring of disease-related branches of the HPO tree

Standardized reannotation of rare, genetically diagnosed diseases

Standardized reannotation of genetically undiagnosed diseases

Patient cohort

HPO information content measures, and disease patient similarity measures

Results

Systematic evaluation and expansion of the HPO structure and terms relevant to IEIs

Directed expansion of PAD terms

Standardized reannotation of rare, genetically diagnosed IEIs

Standardized reannotation of genetically undiagnosed PADs

Patient-disease matching

Phenotype-driven disease classification

Discussion

Conclusions

This work was supported by the European Research Council (ERC Consolidator Grant no. 820074 “iDysChart” to K.B.), by the Austrian Science Fund (FWF) project P 29951-B30 (to K.B.), and by funding from the European Union's Horizon 2020 research and innovation program under the EJP RD COFUND-EJP N° 825575 (to C.B.). Additional financial support for the workshops was granted by the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, the European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA), and the European Society for Immunodeficiencies (ESID).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 149 - N° 1

P. 369-378 - janvier 2022 Retour au numéro

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Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity - 05/01/22

Abstract

Background

Objectives

Methods

Results

Conclusions

Plan

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