Objectivizing issues in the diagnosis of complex rare diseases: lessons learned from testing existing diagnosis support systems on ciliopathies.
Artificial intelligence
Ciliopathy
Clinical decision support
Early diagnosis
Electronic health record
External evaluation
Human phenotype ontology
Patient similarity
Rare diseases
Journal
BMC medical informatics and decision making
ISSN: 1472-6947
Titre abrégé: BMC Med Inform Decis Mak
Pays: England
ID NLM: 101088682
Informations de publication
Date de publication:
24 May 2024
24 May 2024
Historique:
received:
30
01
2024
accepted:
17
05
2024
medline:
25
5
2024
pubmed:
25
5
2024
entrez:
24
5
2024
Statut:
epublish
Résumé
There are approximately 8,000 different rare diseases that affect roughly 400 million people worldwide. Many of them suffer from delayed diagnosis. Ciliopathies are rare monogenic disorders characterized by a significant phenotypic and genetic heterogeneity that raises an important challenge for clinical diagnosis. Diagnosis support systems (DSS) applied to electronic health record (EHR) data may help identify undiagnosed patients, which is of paramount importance to improve patients' care. Our objective was to evaluate three online-accessible rare disease DSSs using phenotypes derived from EHRs for the diagnosis of ciliopathies. Two datasets of ciliopathy cases, either proven or suspected, and two datasets of controls were used to evaluate the DSSs. Patient phenotypes were automatically extracted from their EHRs and converted to Human Phenotype Ontology terms. We tested the ability of the DSSs to diagnose cases in contrast to controls based on Orphanet ontology. A total of 79 cases and 38 controls were selected. Performances of the DSSs on ciliopathy real world data (best DSS with area under the ROC curve = 0.72) were not as good as published performances on the test set used in the DSS development phase. None of these systems obtained results which could be described as "expert-level". Patients with multisystemic symptoms were generally easier to diagnose than patients with isolated symptoms. Diseases easily confused with ciliopathy generally affected multiple organs and had overlapping phenotypes. Four challenges need to be considered to improve the performances: to make the DSSs interoperable with EHR systems, to validate the performances in real-life settings, to deal with data quality, and to leverage methods and resources for rare and complex diseases. Our study provides insights into the complexities of diagnosing highly heterogenous rare diseases and offers lessons derived from evaluation existing DSSs in real-world settings. These insights are not only beneficial for ciliopathy diagnosis but also hold relevance for the enhancement of DSS for various complex rare disorders, by guiding the development of more clinically relevant rare disease DSSs, that could support early diagnosis and finally make more patients eligible for treatment.
Sections du résumé
BACKGROUND
BACKGROUND
There are approximately 8,000 different rare diseases that affect roughly 400 million people worldwide. Many of them suffer from delayed diagnosis. Ciliopathies are rare monogenic disorders characterized by a significant phenotypic and genetic heterogeneity that raises an important challenge for clinical diagnosis. Diagnosis support systems (DSS) applied to electronic health record (EHR) data may help identify undiagnosed patients, which is of paramount importance to improve patients' care. Our objective was to evaluate three online-accessible rare disease DSSs using phenotypes derived from EHRs for the diagnosis of ciliopathies.
METHODS
METHODS
Two datasets of ciliopathy cases, either proven or suspected, and two datasets of controls were used to evaluate the DSSs. Patient phenotypes were automatically extracted from their EHRs and converted to Human Phenotype Ontology terms. We tested the ability of the DSSs to diagnose cases in contrast to controls based on Orphanet ontology.
RESULTS
RESULTS
A total of 79 cases and 38 controls were selected. Performances of the DSSs on ciliopathy real world data (best DSS with area under the ROC curve = 0.72) were not as good as published performances on the test set used in the DSS development phase. None of these systems obtained results which could be described as "expert-level". Patients with multisystemic symptoms were generally easier to diagnose than patients with isolated symptoms. Diseases easily confused with ciliopathy generally affected multiple organs and had overlapping phenotypes. Four challenges need to be considered to improve the performances: to make the DSSs interoperable with EHR systems, to validate the performances in real-life settings, to deal with data quality, and to leverage methods and resources for rare and complex diseases.
CONCLUSION
CONCLUSIONS
Our study provides insights into the complexities of diagnosing highly heterogenous rare diseases and offers lessons derived from evaluation existing DSSs in real-world settings. These insights are not only beneficial for ciliopathy diagnosis but also hold relevance for the enhancement of DSS for various complex rare disorders, by guiding the development of more clinically relevant rare disease DSSs, that could support early diagnosis and finally make more patients eligible for treatment.
Identifiants
pubmed: 38789985
doi: 10.1186/s12911-024-02538-8
pii: 10.1186/s12911-024-02538-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
134Subventions
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Agence Nationale de la Recherche
ID : ANR-17-RHUS-0002
Organisme : Deutsche Forschungsgemeinschaft
ID : PE 3135/1-1
Informations de copyright
© 2024. The Author(s).
Références
RARE Disease Facts. Global Genes. https://globalgenes.org/rare-disease-facts/ . Cited 2022 Jul 8.
Colbaugh R, Glass K, Rudolf C. Tremblay Volv Global, Lausanne, Switzerland M. Learning to identify rare disease patients from electronic health records. AMIA Annu Symp Proc. 2018;2018:340–7.
pubmed: 30815073
pmcid: 6371307
Neuraz A, Lerner I, Digan W, Paris N, Tsopra R, Rogier A, et al. Natural language processing for rapid response to emergent diseases: case study of calcium channel blockers and hypertension in the COVID-19 pandemic. J Med Internet Res. 2020;22(8):e20773.
pubmed: 32759101
pmcid: 7431235
doi: 10.2196/20773
Escudié JB, Rance B, Malamut G, Khater S, Burgun A, Cellier C, et al. A novel data-driven workflow combining literature and electronic health records to estimate comorbidities burden for a specific disease: a case study on autoimmune comorbidities in patients with celiac disease. BMC Med Inf Decis Mak. 2017;17:140.
doi: 10.1186/s12911-017-0537-y
Yang DD, Rio M, Michot C, Boddaert N, Yacoub W, Garcelon N, et al. Natural history of Myhre syndrome. Orphanet J Rare Dis. 2022;17(1):304.
pubmed: 35907855
pmcid: 9338657
doi: 10.1186/s13023-022-02447-x
Lo Barco T, Kuchenbuch M, Garcelon N, Neuraz A, Nabbout R. Improving early diagnosis of rare diseases using Natural Language Processing in unstructured medical records: an illustration from Dravet syndrome. Orphanet J Rare Dis. 2021;16(1):309.
pubmed: 34256808
doi: 10.1186/s13023-021-01936-9
Lo Barco T, Garcelon N, Neuraz A, Nabbout R. Natural history of rare diseases using natural language processing of narrative unstructured electronic health records: The example of Dravet syndrome. Epilepsia. 2023. https://pubmed.ncbi.nlm.nih.gov/38065926/ . Cited 2024 Jan 4.
Zanello G, Chan CH, Pearce DA. Recommendations from the IRDiRC Working group on methodologies to assess the impact of diagnoses and therapies on rare disease patients. Orphanet J Rare Dis. 2022;17:181.
pubmed: 35526001
pmcid: 9078009
doi: 10.1186/s13023-022-02337-2
Zhou S, Wang N, Wang L, Liu H, Zhang R. CancerBERT: a cancer domain-specific language model for extracting breast cancer phenotypes from electronic health records. J Am Med Inf Assoc. 2022:1208-16.
Kohane IS, Aronow BJ, Avillach P, Beaulieu-Jones BK, Bellazzi R, Bradford RL, et al. What every reader should know about studies using Electronic Health Record Data but May be afraid to ask. J Med Internet Res. 2021;23(3):e22219.
pubmed: 33600347
pmcid: 7927948
doi: 10.2196/22219
Faviez C, Chen X, Garcelon N, Neuraz A, Knebelmann B, Salomon R, et al. Diagnosis support systems for rare diseases: a scoping review. Orphanet J Rare Dis. 2020;15(1):94.
pubmed: 32299466
pmcid: 7164220
doi: 10.1186/s13023-020-01374-z
Robinson PN, Köhler S, Bauer S, Seelow D, Horn D, Mundlos S. The human phenotype ontology: a tool for annotating and analyzing human hereditary disease. Am J Hum Genet. 2008;83(5):610–5.
pubmed: 18950739
pmcid: 2668030
doi: 10.1016/j.ajhg.2008.09.017
Movaghar A, Page D, Brilliant M, Mailick M. Advancing artificial intelligence-assisted pre-screening for fragile X syndrome. BMC Med Inf Decis Mak. 2022;22(1):152.
doi: 10.1186/s12911-022-01896-5
Huda A, Castaño A, Niyogi A, Schumacher J, Stewart M, Bruno M, et al. A machine learning model for identifying patients at risk for wild-type transthyretin amyloid cardiomyopathy. Nat Commun. 2021;12(1):2725.
pubmed: 33976166
pmcid: 8113237
doi: 10.1038/s41467-021-22876-9
Willis C, Watanabe AH, Hughes J, Nolen K, O’Meara J, Schepart A, et al. Applying diagnosis support systems in electronic health records to identify wild-type transthyretin amyloid cardiomyopathy risk. Future Cardiol. 2022;18(5):367–76.
pubmed: 35098741
doi: 10.2217/fca-2021-0122
Jefferies JL, Spencer AK, Lau HA, Nelson MW, Giuliano JD, Zabinski JW, et al. A new approach to identifying patients with elevated risk for fabry disease using a machine learning algorithm. Orphanet J Rare Dis. 2021;16(1):518.
pubmed: 34930374
pmcid: 8686369
doi: 10.1186/s13023-021-02150-3
Rider NL, Cahill G, Motazedi T, Wei L, Kurian A, Noroski LM, et al. PI Prob: a risk prediction and clinical guidance system for evaluating patients with recurrent infections. PLoS ONE. 2021;16(2):e0237285.
pubmed: 33591972
pmcid: 7886140
doi: 10.1371/journal.pone.0237285
García-García E, González-Romero GM, Martín-Pérez EM, Zapata Cornejo E, de D, Escobar-Aguilar G. Cárdenas Bonnet MF. Real-world data and machine learning to predict cardiac amyloidosis. Int J Environ Res Public Health. 2021;18(3):908.
pubmed: 33494357
pmcid: 7908075
doi: 10.3390/ijerph18030908
Doyle OM, van der Laan R, Obradovic M, McMahon P, Daniels F, Pitcher A, et al. Identification of potentially undiagnosed patients with nontuberculous mycobacterial lung disease using machine learning applied to primary care data in the UK. Eur Respir J. 2020;56(4):2000045.
pubmed: 32430411
doi: 10.1183/13993003.00045-2020
Cohen AM, Chamberlin S, Deloughery T, Nguyen M, Bedrick S, Meninger S, et al. Detecting rare diseases in electronic health records using machine learning and knowledge engineering: case study of acute hepatic porphyria. PLoS ONE. 2020;15(7):e0235574.
pubmed: 32614911
pmcid: 7331997
doi: 10.1371/journal.pone.0235574
Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol. 2017;18(9):533–47.
pubmed: 28698599
pmcid: 5851292
doi: 10.1038/nrm.2017.60
Powles-Glover N. Cilia and ciliopathies: Classic examples linking phenotype and genotype—An overview. Reprod Toxicol. 2014;48:98–105.
pubmed: 24859270
doi: 10.1016/j.reprotox.2014.05.005
McConnachie DJ. Ciliopathies and the Kidney: A Review. Am J Kidney Dis. 2021;77:10.
Snoek R, van Setten J, Keating BJ, Israni AK, Jacobson PA, Oetting WS, et al. NPHP1 (Nephrocystin-1) gene deletions cause adult-onset ESRD. J Am Soc Nephrol. 2018;29(6):1772–9.
pubmed: 29654215
pmcid: 6054334
doi: 10.1681/ASN.2017111200
Petzold F, Billot K, Chen X, Henry C, Filhol E, Martin Y, et al. The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies. Kidney Int. 2023;104(2):378–87.
pubmed: 37230223
doi: 10.1016/j.kint.2023.05.007
Garcia H, Serafin AS, Silbermann F, Porée E, Viau A, Mahaut C, et al. Agonists of prostaglandin E2 receptors as potential first in class treatment for nephronophthisis and related ciliopathies. Proc Natl Acad Sci U S A. 2022;119(18):e2115960119.
pubmed: 35482924
pmcid: 9170064
doi: 10.1073/pnas.2115960119
Crigger E, Reinbold K, Hanson C, Kao A, Blake K, Irons M. Trustworthy augmented intelligence in health care. J Med Syst. 2022;46(2):12.
pubmed: 35020064
pmcid: 8755670
doi: 10.1007/s10916-021-01790-z
Garcelon N, Neuraz A, Salomon R, Faour H, Benoit V, Delapalme A, et al. A clinician friendly data warehouse oriented toward narrative reports: Dr. Warehouse. J Biomed Inform. 2018;80:52–63.
pubmed: 29501921
doi: 10.1016/j.jbi.2018.02.019
Morley TJ, Han L, Castro VM, Morra J, Perlis RH, Cox NJ, et al. Phenotypic signatures in clinical data enable systematic identification of patients for genetic testing. Nat Med. 2021;27(6):1097–104.
pubmed: 34083811
pmcid: 8981189
doi: 10.1038/s41591-021-01356-z
Bodenreider O. The Unified Medical Language System (UMLS): integrating biomedical terminology. Nucleic Acids Res. 2004;32(Database issue):D267–270.
pubmed: 14681409
pmcid: 308795
doi: 10.1093/nar/gkh061
Chen X, Garcelon N, Neuraz A, Billot K, Lelarge M, Bonald T, et al. Phenotypic similarity for rare disease: ciliopathy diagnoses and subtyping. J Biomed Inf. 2019;100:103308.
doi: 10.1016/j.jbi.2019.103308
Chen X, Faviez C, Vincent M, Garcelon N, Saunier S, Burgun A. Identification of similar patients through Medical Concept Embedding from electronic health records: a feasibility study for rare disease diagnosis. Stud Health Technol Inf. 2021;281:600–4.
Köhler S, Schulz MH, Krawitz P, Bauer S, Dölken S, Ott CE, et al. Clinical diagnostics in human genetics with semantic similarity searches in ontologies. Am J Hum Genet. 2009;85(4):457–64.
pubmed: 19800049
pmcid: 2756558
doi: 10.1016/j.ajhg.2009.09.003
Chen J, Xu H, Jegga A, Zhang K, White PS, Zhang G. Novel phenotype-disease matching tool for rare genetic diseases. Genet Med. 2019;21(2):339–46.
pubmed: 29895857
doi: 10.1038/s41436-018-0050-4
Fujiwara T, Yamamoto Y, Kim JD, Buske O, Takagi T, PubCaseFinder:. A case-report-based, phenotype-driven differential-diagnosis system for Rare diseases. Am J Hum Genet. 2018;06(3):389–99.
doi: 10.1016/j.ajhg.2018.08.003
[Orphanet: a European database for rare diseases]. - Abstract - Europe PMC. https://europepmc.org/abstract/med/18389888 . Cited 2019 Oct 24.
Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA. Online mendelian inheritance in man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 2005;33(Database issue):D514–517.
pubmed: 15608251
doi: 10.1093/nar/gki033
R Core Team. R: A Language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2020. https://www.R-project.org/ .
Bauer S, Köhler S, Schulz MH, Robinson PN. Bayesian ontology querying for accurate and noise-tolerant semantic searches. Bioinformatics. 2012;28(19):2502–8.
pubmed: 22843981
pmcid: 3463114
doi: 10.1093/bioinformatics/bts471
Arts HH, Knoers NVAM. Current insights into renal ciliopathies: what can genetics teach us? Pediatr Nephrol. 2013;28(6):863–74.
pubmed: 22829176
doi: 10.1007/s00467-012-2259-9
Liu C, Ta CN, Havrilla JM, Nestor JG, Spotnitz ME, Geneslaw AS, et al. OARD: open annotations for rare diseases and their phenotypes based on real-world data. Am J Hum Genet. 2022;109(9):1591–604.
pubmed: 35998640
pmcid: 9502051
doi: 10.1016/j.ajhg.2022.08.002
Dembrower K, Crippa A, Colón E, Eklund M, Strand F, ScreenTrustCAD trial consortium. artificial intelligence for breast cancer detection in screening mammography in Sweden: a prospective, population-based, paired-reader, non-inferiority study. Lancet Digit Health. 2023;5(10):e703–11.
pubmed: 37690911
doi: 10.1016/S2589-7500(23)00153-X
Lång K, Josefsson V, Larsson AM, Larsson S, Högberg C, Sartor H, et al. Artificial intelligence-supported screen reading versus standard double reading in the Mammography screening with Artificial Intelligence trial (MASAI): a clinical safety analysis of a randomised, controlled, non-inferiority, single-blinded, screening accuracy study. Lancet Oncol. 2023;24(8):936–44.
pubmed: 37541274
doi: 10.1016/S1470-2045(23)00298-X
Weber GM, Hong C, Xia Z, Palmer NP, Avillach P, L’Yi S, et al. International comparisons of laboratory values from the 4CE collaborative to predict COVID-19 mortality. NPJ Digit Med. 2022;5(1):74.
pubmed: 35697747
pmcid: 9192605
doi: 10.1038/s41746-022-00601-0
Adams R, Henry KE, Sridharan A, Soleimani H, Zhan A, Rawat N, et al. Prospective, multi-site study of patient outcomes after implementation of the TREWS machine learning-based early warning system for sepsis. Nat Med. 2022;28(7):1455–60.
pubmed: 35864252
doi: 10.1038/s41591-022-01894-0
Schaaf J, Sedlmayr M, Schaefer J, Storf H. Diagnosis of Rare diseases: a scoping review of clinical decision support systems. Orphanet J Rare Dis. 2020;15(1):263.
pubmed: 32972444
pmcid: 7513302
doi: 10.1186/s13023-020-01536-z
Youssef A, Pencina M, Thakur A, Zhu T, Clifton D, Shah NH. External validation of AI models in health should be replaced with recurring local validation. Nat Med. 2023;29(11):2686–7.
pubmed: 37853136
doi: 10.1038/s41591-023-02540-z
Zaar O, Larson A, Polesie S, Saleh K, Tarstedt M, Olives A, et al. Evaluation of the diagnostic accuracy of an online Artificial Intelligence Application for skin disease diagnosis. Acta Derm Venereol. 2020;100(16):adv00260.
pubmed: 32852557
doi: 10.2340/00015555-3624
Steele L, Velazquez-Pimentel D, Thomas BR. Do AI models recognise rare, aggressive skin cancers? An assessment of a direct-to-consumer app in the diagnosis of Merkel cell carcinoma and amelanotic melanoma. J Eur Acad Dermatol Venereol. 2021;35(12):e877–9.
pubmed: 34242437
doi: 10.1111/jdv.17517
Zemojtel T, Köhler S, Mackenroth L, Jäger M, Hecht J, Krawitz P, et al. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci Transl Med. 2014;6(252):252ra123.
pubmed: 25186178
pmcid: 4512639
doi: 10.1126/scitranslmed.3009262
Ullah MZ, Aono M, Seddiqui MH. Estimating a ranked list of human genetic diseases by associating phenotype-gene with gene-disease bipartite graphs. ACM Trans Intell Syst Technol. 2015;6(4):56.
doi: 10.1145/2700487
Yang H, Robinson PN, Wang K. Phenolyzer: phenotype-based prioritization of candidate genes for human diseases. Nat Methods. 2015;12(9):841–3.
pubmed: 26192085
pmcid: 4718403
doi: 10.1038/nmeth.3484
Pinol M, Alves R, Teixido I, Mateo J, Solsona F, Vilaprinyo E. Rare disease discovery: an optimized disease ranking system. IEEE Trans Ind Inf. 2017;13(3):1184–92.
doi: 10.1109/TII.2017.2686380
Garcelon N, Burgun A, Salomon R, Neuraz A. Electronic health records for the diagnosis of rare diseases. Kidney Int. 2020;97(4):676–86.
pubmed: 32111372
doi: 10.1016/j.kint.2019.11.037
Schaaf J, Sedlmayr M, Sedlmayr B, Storf H. User-centred development of a diagnosis support system for rare diseases. dHealth. 2022;2022:11–8.
Kim E, Rubinstein SM, Nead KT, Wojcieszynski AP, Gabriel PE, Warner JL. The evolving use of electronic health records (EHR) for research. Semin Radiat Oncol. 2019;29(4):354–61.
pubmed: 31472738
doi: 10.1016/j.semradonc.2019.05.010
Sarker A. LexExp: a system for automatically expanding concept lexicons for noisy biomedical texts. Bioinformatics. 2021;37(16):2499–501.
pubmed: 33244602
doi: 10.1093/bioinformatics/btaa995
Faviez C, Vincent M, Garcelon N, Michot C, Baujat G, Cormier-Daire V, et al. Enriching UMLS-based phenotyping of rare diseases using deep-learning: evaluation on Jeune syndrome. Stud Health Technol Inf. 2022;294:844–8.
Chen X, Faviez C, Vincent M, Briseño-Roa L, Faour H, Annereau JP et al. Patient-Patient similarity-based screening of a clinical data warehouse to support ciliopathy diagnosis. frontiers in pharmacology. 2022;13. https://www.frontiersin.org/article/ https://doi.org/10.3389/fphar.2022.786710 . Cited 2022 Apr 4.
Faviez C, Vincent M, Garcelon N, Boyer O, Knebelmann B, Heidet L, et al. Performance and clinical utility of a new supervised machine-learning pipeline in detecting rare ciliopathy patients based on deep phenotyping from electronic health records and semantic similarity. Orphanet J Rare Dis. 2024;19(1):55.
pubmed: 38336713
pmcid: 10858490
doi: 10.1186/s13023-024-03063-7
Chen X, Faviez C, Vincent M, Saunier S, Garcelon N, Burgun A. Improving patient similarity using different modalities of phenotypes extracted from clinical narratives. Stud Health Technol Inf. 2023;302:1037–41.
Li MM, Huang K, Zitnik M. Graph representation learning in biomedicine and healthcare. Nat Biomed Eng. 2022;6(12):1353–69.
pubmed: 36316368
pmcid: 10699434
doi: 10.1038/s41551-022-00942-x
Buphamalai P, Kokotovic T, Nagy V, Menche J. Network analysis reveals rare disease signatures across multiple levels of biological organization. Nat Commun. 2021;12(1):6306.
pubmed: 34753928
pmcid: 8578255
doi: 10.1038/s41467-021-26674-1
Hu L, Pan X, Tang Z, Luo X. A fast fuzzy clustering algorithm for Complex Networks via a generalized momentum method. IEEE Trans Fuzzy Syst. 2022;30(9):3473–85.
doi: 10.1109/TFUZZ.2021.3117442
Yang Y, Su X, Zhao B, Li G, Hu P, Zhang J, et al. Fuzzy-based deep attributed graph clustering. IEEE Trans Fuzzy Syst. 2024;32(4):1951–64.
doi: 10.1109/TFUZZ.2023.3338565
Decherchi S, Pedrini E, Mordenti M, Cavalli A, Sangiorgi L. Opportunities and challenges for Machine Learning in Rare diseases. Front Med (Lausanne). 2021;8:747612.
pubmed: 34676229
doi: 10.3389/fmed.2021.747612