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This research aimed to elicit perspectives from PKU medical experts regarding approaches for CEA modeling, to inform development of a face-validated model structure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a modified e-Delphi study, clinical experts rated their agreement\/disagreement with 14 statements on clinical outcomes, diet, target population, blood phenylalanine (Phe)-level classification, and treatment discontinuation. Separately, a survey of a broader sample of experts elicited perspectives on the prevalence of PKU comorbidities, and biological plausibility of the association of surrogate outcomes with comorbidity risk. Insights informed development of the conceptual structure and parameters for a CEA model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the modified e-Delphi study, participants (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200911) achieved consensus (\u2265\u200970% agreement\/disagreement) on statements on the associations of blood Phe levels with outcomes, unmet need, mechanisms for the association of PKU with chronic comorbidities, and medical management approaches. In the survey (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200930), \u2265\u200970% of participants agreed that prevalence of comorbidities is higher in PKU vs. the general population, and that increased natural-protein consumption may reduce comorbidity risk, including for depression, osteoporosis, overweight, anemia, and type two diabetes mellitus. Findings informed development of a CEA model structure comprising five blood Phe level-defined health states (range: \u2264120 \u00b5mol\/L to &gt;\u20091200 \u00b5mol\/L), associated with four classes of patient-relevant clinical outcomes in PKU: contemporaneous symptoms\/manifestations, intellectual disability, comorbidities, and diet liberalization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In this research, perspectives were elicited from medical experts in PKU to develop a clinically informed, face-validated conceptual model structure for CEA, and to identify associated parameters. The resulting\n                      <jats:italic>de novo<\/jats:italic>\n                      economic model allows for valuation of numerous important patient-relevant outcomes, enabling modeling of the heterogeneous drivers of unmet need in PKU. The structured expert-elicitation approach used in this research, and documentation of the influence of perspectives elicited on model structure and parameters, support the validity of the model for application in economic evaluation of interventions for PKU.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04423-1","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T16:44:52Z","timestamp":1780073092000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of a face-validated conceptual model structure for economic evaluation in phenylketonuria, through expert elicitation"],"prefix":"10.1186","volume":"21","author":[{"given":"Ania C.","family":"Muntau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupam","family":"Chakrapani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Hamazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Lah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle J.","family":"Ruebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Vijay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto T.","family":"Zori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Feillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Longo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hope","family":"Northrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Hollander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"O\u2019Connell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Woolley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0290-4583","authenticated-orcid":false,"given":"Ioannis","family":"Tomazos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"issue":"1","key":"4423_CR1","first-page":"31","volume":"29","author":"RA Williams","year":"2008","unstructured":"Williams RA, Mamotte CD, Burnett JR. 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Am J Hum Genet. 2020;107(2):234\u201350.","journal-title":"Am J Hum Genet"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04423-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04423-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04423-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T01:47:49Z","timestamp":1785808069000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13023-026-04423-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4423"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04423-1","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]},"assertion":[{"value":"15 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The Delphi panel study and clinical-expert survey study were reviewed by the WCG Institutional Review Board and received waivers of the ethical review requirements. For both the survey and the Delphi panel, all participants provided informed consent prior to participating in the process.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ioannis Tomazos is an employee of PTC Therapeutics Inc. Rongrong Zhang was an employee of PTC Therapeutics Inc. at the time of research completion. Thomas O\u2019Connell and Jonathan J. Woolley are employees of Medicus Economics which was contracted by PTC Therapeutics Inc. for the conduct of this research. Ania C. Muntau participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Actelion, Applied Pharma Research, Arla Food, BioMarin, Censa, Merck Serono, Nestl\u00e9 Health Science (SHS), PTC Therapeutics, Retrophin (now Travere Therapeutics), Jnana Therapeutics (now Otsuka), Pluvia, and Synlogic Therapeutics and received research grants from: Dr Sch\u00e4r, Merck Serono, Nutricia, SHS, and Vitaflo. Takashi Hamazaki has participated in advisory boards and received clinical trial support from PTC Therapeutics Inc., and has also received funding and research support from BioMarin Pharmaceuticals Inc., Sanofi, and JCR Pharma. Melissa Lah participated as a clinical trial investigator for BioMarin, Homology Medicines, Moderna, and PTC Therapeutics; received consulting payments from BioMarin, PTC Therapeutics, Maze Therapeutics and Travere Therapeutics; and travel support from BioMarin and PTC Therapeutics. Danielle J. Ruebel has served as an advisory board participant, consultant, and\/or paid speaker for PTC Therapeutics and Biomarin Pharmaceutical. Roberto T. Zori reports support as principal investigator on studies for BioMarin Pharmaceutical, PTC Therapeutics, Inc and Jnana Therapeutics. Francois Feillet reports serving on scientifc boards for Biomarin, Genzyme, Vitaflo, Danone, Alexion, Recordati, and Jnana Therapeutics; a grant from Recordati (to INSERM); and participation of the DSMB of Aphenity study (PTC Therapeutics). Nicola Longo reports clinical trials support from Amicus Therapeutics, Astellas, BioMarin, Chiesi\/Protalix, Genzyme\/Sanofi, iECure, Moderna, Otsuka\/ Jnana Therapeutics, PTC Therapeutics, Spark Therapeutics, Ultragenyx, and UniQure; serving on advisory boards for Amicus Therapeutics, Astellas, BioMarin, Chiesi\/Protalix, Genzyme\/Sanofi, Jaguar Gene Therapy, Maze therapeutics, Moderna, Otsuka\/ Jnana Therapeutics, PTC Therapeutics, and Ultragenyx; and travel support from Astellas, Chiesi\/Protalix, Genzyme\/Sanofi, Otsuka\/ Jnana Therapeutics, and PTC Therapeutics. Suzanne Hollander has served as an advisory board participant, consultant, and\/or paid speaker for PTC Therapeutics, Biomarin Pharmaceutical, Sanofi, and Vitaflo North America. Anupam Chakrapani, Suresh Vijay and Hope Northrup declare no conflicts.","order":3,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"262"}}