{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:26:21Z","timestamp":1780471581881,"version":"3.54.1"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Alkaptonuria (AKU) is a rare inherited metabolic disorder characterized by progressive musculoskeletal damage, chronic pain, and functional heterogeneity. To better quantify this variability, we introduced the concept of the functional age gap, defined as the difference between chronological age and a data-derived estimate of functional age. The study included 134 patients with AKU from the ApreciseKUre database. Functional age was calculated by mapping Health Assessment Questionnaire Disability Index (HAQ-DI) and Knee Injury and Osteoarthritis Outcome Score (KOOS) values to age-referenced normative data. Most patients (94.8%) showed a positive functional age gap, with a mean difference of 15 years, which indicates a functionally older profile than expected for their chronological age. A bagging ensemble of decision trees was then used to explore relationships between clinical variables and functional age gap severity. The model achieved moderate but stable classification performance across repeated stratified cross-validation (64%), consistent with an exploratory analysis in a small rare-disease cohort. SHapley Additive exPlanations analysis identified age, AKUSSI spinal pain, AKUSSI joint pain, Schober test, and hip and knee activity as the most influential predictors. These findings support the functional age gap as an interpretable, hypothesis-generating descriptive metric for functional assessment in AKU, while its predictive utility for individual patient stratification will require validation in larger and longitudinal cohorts.<\/jats:p>","DOI":"10.3390\/bioengineering13060604","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T16:06:08Z","timestamp":1779465968000},"page":"604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantifying the Functional Gap in Alkaptonuria Through Machine Learning and Clinical Data Integration"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9281-034X","authenticated-orcid":false,"given":"Anna","family":"Visibelli","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6969-1493","authenticated-orcid":false,"given":"Rebecca","family":"Finetti","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0009-4011","authenticated-orcid":false,"given":"Bianca","family":"Roncaglia","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Trezza","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Marzocchi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy"},{"name":"UOC Laboratorio Patologia Clinica, Ospedale S. Maria alle Scotte, AOU Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-7107","authenticated-orcid":false,"given":"Ottavia","family":"Spiga","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy"},{"name":"Centro della Scienza e della Tecnica, Polo Universitario Grossetano, Via Ginori 41, 58100 Grosseto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-9086","authenticated-orcid":false,"given":"Annalisa","family":"Santucci","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy"},{"name":"Industry 4.0 Competence Center ARTES 4.0, Viale Rinaldo Piaggio, 56025 Pontedera, Italy"},{"name":"MetabERN, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1016\/S0140-6736(01)41972-6","article-title":"The incidence of alkaptonuria: A study in chemical individuality","volume":"160","author":"Garrod","year":"1902","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ng0996-19","article-title":"The molecular basis of alkaptonuria","volume":"14","author":"Granadino","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1002\/humu.21120","article-title":"Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria","volume":"30","author":"Vilboux","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/art.1780040202","article-title":"Studies of alcaptonuria: A genetic study of 58 cases occurring in eight generations of seven inter-related Dominican kindreds","volume":"4","author":"Milch","year":"1961","journal-title":"Arthritis Rheum."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.1002\/jcp.29575","article-title":"Homogentisic acid affects human osteoblastic functionality by oxidative stress and alteration of the Wnt\/\u03b2-catenin signaling pathway","volume":"235","author":"Schiavone","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"108416","DOI":"10.1016\/j.abb.2020.108416","article-title":"Mechanisms involved in the unbalanced redox homeostasis in osteoblastic cellular model of alkaptonuria","volume":"690","author":"Schiavone","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1076288","DOI":"10.1016\/j.ymgme.2023.107628","article-title":"Biochemical and molecular confirmation of alkaptonuria in a Sumatran orangutan (Pongo abelii)","volume":"139","author":"Fayette","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11937","DOI":"10.1002\/anie.202000618","article-title":"Pigmentation chemistry and radical-based collagen degradation in alkaptonuria and osteoarthritic cartilage","volume":"59","author":"Chow","year":"2020","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.semcdb.2016.02.020","article-title":"Alkaptonuria: An example of a \u201cfundamental disease\u201d\u2014A rare disease with important lessons for more common disorders","volume":"52","author":"Gallagher","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1056\/NEJMoa021736","article-title":"Natural history of alkaptonuria","volume":"347","author":"Phornphutkul","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.crstbi.2022.08.001","article-title":"HGDiscovery: An online tool providing functional and phenotypic information on novel variants of homogentisate 1,2-dioxigenase","volume":"4","author":"Karmakar","year":"2022","journal-title":"Curr. Res. Struct. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1136\/bmjinnov-2018-000324","article-title":"Subclinical ochronosis features in alkaptonuria: A cross-sectional study","volume":"5","author":"Cox","year":"2019","journal-title":"BMJ Innov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1007\/s10545-011-9374-9","article-title":"Natural history of alkaptonuria revisited: Analyses based on scoring systems","volume":"34","author":"Ranganath","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_14","first-page":"2280","article-title":"Musculoskeletal findings and disability in alkaptonuria","volume":"33","author":"Perry","year":"2006","journal-title":"J. Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Maggino, F. (2023). Quality of life (QOL), an overview. Encyclopedia of Quality of Life and Well-Being Research, Springer.","DOI":"10.1007\/978-3-031-17299-1"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s12955-024-02324-0","article-title":"Assessing the effectiveness of measurement scales in evaluating the health-related quality of life in rare disease patients after treatment: A systematic review","volume":"22","author":"Dumbuya","year":"2024","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13023-020-1305-0","article-title":"Machine learning application for development of a data-driven predictive model able to investigate quality of life scores in a rare disease","volume":"15","author":"Spiga","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_18","first-page":"73","article-title":"A patient survey on the impact of alkaptonuria symptoms as perceived by the patients and their experiences of receiving diagnosis and care","volume":"53","author":"Rudebeck","year":"2020","journal-title":"JIMD Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dumbuya, J.S., Zeng, C., Deng, L., Li, Y., Chen, X., Ahmad, B., and Lu, J. (2025). The impact of rare diseases on the quality of life in paediatric patients: Current status. Front. Public Health, 13.","DOI":"10.3389\/fpubh.2025.1531583"},{"key":"ref_20","first-page":"S14","article-title":"The Health Assessment Questionnaire (HAQ)","volume":"23","author":"Bruce","year":"2005","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.joca.2016.03.010","article-title":"Knee Injury and Osteoarthritis Outcome Score (KOOS): Systematic review and meta-analysis of measurement properties","volume":"24","author":"Collins","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1007\/s10545-011-9367-8","article-title":"A quantitative assessment of alkaptonuria: Testing the reliability of two disease severity scoring systems","volume":"34","author":"Cox","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., and Peters, V. (2018). Alkaptonuria Severity Score Index revisited: Analysing the AKUSSI and its subcomponent features. JIMD Reports, Springer.","DOI":"10.1007\/978-3-662-57880-3"},{"key":"ref_24","first-page":"361","article-title":"Improving the clinical accuracy and flexibility of the alkaptonuria severity score index","volume":"63","author":"Cant","year":"2022","journal-title":"JIMD Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"137","DOI":"10.4103\/2229-3485.86879","article-title":"Patient-reported outcomes: A new era in clinical research","volume":"2","author":"Deshpande","year":"2011","journal-title":"Perspect. Clin. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Visibelli, A., Roncaglia, B., Spiga, O., and Santucci, A. (2023). The impact of artificial intelligence in the odyssey of rare diseases. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030887"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Vabalas, A., Gowen, E., Poliakoff, E., and Casson, A.J. (2019). Machine learning algorithm validation with a limited sample size. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224365"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rajput, D., Wang, W.J., and Chen, C.C. (2023). Evaluation of a decided sample size in machine learning applications. BMC Bioinform., 24.","DOI":"10.1186\/s12859-023-05156-9"},{"key":"ref_29","first-page":"e2174v1","article-title":"Towards an integrated interactive database for the search of stratification biomarkers in alkaptonuria","volume":"4","author":"Cicaloni","year":"2016","journal-title":"PeerJ Prepr."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Spiga, O., Cicaloni, V., Bernini, A., Zatkova, A., and Santucci, A. (2017). ApreciseKUre: An approach of precision medicine in a rare disease. BMC Med. Inform. Decis. Mak., 17.","DOI":"10.1186\/s12911-017-0438-0"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Visibelli, A., Cicaloni, V., Spiga, O., and Santucci, A. (2022). Computational approaches integrated in a digital ecosystem platform for a rare disease. Front. Mol. Med., 2.","DOI":"10.3389\/fmmed.2022.827340"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/S2213-8587(20)30228-X","article-title":"Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): An international, multicentre, open-label, randomised controlled trial","volume":"8","author":"Ranganath","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.knee.2023.06.004","article-title":"Knee injury and osteoarthritis outcome score (KOOS): National record-based reference values","volume":"43","author":"Larsen","year":"2023","journal-title":"Knee"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/art.20048","article-title":"Normative values for the Health Assessment Questionnaire Disability Index: Benchmarking disability in the general population","volume":"50","author":"Krishnan","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sarang, P. (2023). Ensemble: Bagging and boosting. Thinking Data Science, Springer.","DOI":"10.1007\/978-3-031-02363-7"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41572-024-00498-x","article-title":"Alkaptonuria","volume":"10","author":"Bernardini","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1145\/3637487","article-title":"Explainable AI for medical data: Current methods, limitations, and future directions","volume":"57","author":"Hossain","year":"2025","journal-title":"ACM Comput. Surv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jclinepi.2021.12.009","article-title":"Design and analysis features used in small population and rare disease trials: A targeted review","volume":"144","author":"Partington","year":"2022","journal-title":"J. Clin. Epidemiol."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/13\/6\/604\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:56:25Z","timestamp":1780469785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/13\/6\/604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["bioengineering13060604"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering13060604","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]}}}