{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:54:53Z","timestamp":1790931293296,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Primary hyperparathyroidism parathyroid hormone (PTH) hypersecretion is difficult to recognise when calcium is normal and difficult to distinguish from secondary hyperparathyroidism once PTH is found to be elevated. These are separate problems arising at separate points in care. We developed and evaluated two interpretable models corresponding to these decision points using an internal\u2013external validation design. Methods: We analysed 2788 adults undergoing PTH testing across three campuses of one hospital (development n = 1843; internal\u2013external validation n = 445 and n = 500); those with an estimated glomerular filtration rate below 30 mL\/min\/1.73 m2 were excluded. PHPT was adjudicated in 504 (18.1%) by two endocrinologists using biochemistry, imaging and histopathology. Model 1, for use before PTH is measured, comprised total calcium, ln(alkaline phosphatase) and age. Model 2, developed in the Main campus subgroup with PTH above the reference limit (&gt;65 pg\/mL, n = 429 of 623), comprised ln(PTH), total calcium and phosphate. Results: Model 1 achieved AUCs of 0.920 in the development cohort and 0.882\u20130.908 in the validation cohorts; because serum calcium contributed to the outcome definition, these estimates reflect agreement with the reference standard rather than independent diagnostic accuracy. Among participants with elevated PTH, Model 2 achieved an AUC of 0.904 in the development cohort and 0.892 in the pooled validation cohort compared with 0.803 and 0.791 for PTH alone, respectively. In the normocalcaemic subgroup, Model 2 achieved an AUC of 0.790 compared with 0.699 for PTH alone. Applied sequentially, the models referred 18.0\u201326.1% of participants while capturing 78.1\u201385.0% of PHPT cases and identified a second-stage subgroup with an observed PHPT prevalence of 93.1\u201395.1%. Conclusions: This two-stage strategy may support further testing and referral for PHPT using routinely available measurements. Prospective validation in broader clinical populations is required before clinical implementation.<\/jats:p>","DOI":"10.3390\/diagnostics16193200","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:15:18Z","timestamp":1790928918000},"page":"3200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Two-Stage Prediction Strategy for Primary Hyperparathyroidism"],"prefix":"10.3390","volume":"16","author":[{"given":"Ruisi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Endocrinology, School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People\u2019s Hospital, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3570","DOI":"10.1210\/jc.2014-1414","article-title":"Diagnosis of asymptomatic primary hyperparathyroidism: Proceedings of the Fourth International Workshop","volume":"99","author":"Eastell","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1210\/jc.2018-01225","article-title":"Primary Hyperparathyroidism","volume":"103","author":"Bilezikian","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1001\/jama.2020.0538","article-title":"Diagnosis and Management of Primary Hyperparathyroidism","volume":"323","author":"Zhu","year":"2020","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1002\/jbmr.4665","article-title":"Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism","volume":"37","author":"Minisola","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_5","first-page":"658","article-title":"Serum calcium and bone: Effect of PTH, phosphate, vitamin D and uremia","volume":"34","author":"Levine","year":"2014","journal-title":"Nefrologia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1345\/aph.1G724","article-title":"Secondary hyperparathyroidism in chronic kidney disease: Focus on clinical consequences and vitamin D therapies","volume":"40","author":"Hudson","year":"2006","journal-title":"Ann. Pharmacother."},{"key":"ref_7","unstructured":"Chinese Society of Osteoporosis and Bone Mineral Research, Metabolic Bone Disease Group, and Chinese Society of Endocrinology (2014). Guideline for the diagnosis and management of primary hyperparathyroidism. Chin. J. Osteoporos. Bone Miner. Res., 7, 187\u2013198. (In Chinese)."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1002\/jbmr.4677","article-title":"Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop","volume":"37","author":"Bilezikian","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1258\/0004563041731619","article-title":"Vitamin D deficiency masking primary hyperparathyroidism","volume":"41","author":"Hannan","year":"2004","journal-title":"Ann. Clin. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.amjsurg.2023.04.004","article-title":"Normohormonal primary hyperparathyroidism: A systematic review and meta-analysis","volume":"226","author":"Nabata","year":"2023","journal-title":"Am. J. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1001\/jamasurg.2016.2310","article-title":"The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism","volume":"151","author":"Wilhelm","year":"2016","journal-title":"JAMA Surg."},{"key":"ref_12","first-page":"438","article-title":"Primary hyperparathyroidism: Diagnosis and management in 2017","volume":"127","author":"Syed","year":"2017","journal-title":"Pol. Arch. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/jbm4.10019","article-title":"Serum Calcium to Phosphorous (Ca\/P) Ratio Is a Simple, Inexpensive, and Accurate Tool in the Diagnosis of Primary Hyperparathyroidism","volume":"2","author":"Madeo","year":"2018","journal-title":"JBMR Plus"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Guo, Y., Wang, Q., Lu, C., Fan, P., Li, J., Luo, X., and Chen, D. (2020). New parathyroid function index for the differentiation of primary and secondary hyperparathyroidism: A case-control study. BMC Endocr. Disord., 20.","DOI":"10.1186\/s12902-019-0487-8"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1016\/j.surg.2012.08.013","article-title":"Calculating an individual maxPTH to aid diagnosis of normocalemic primary hyperparathyroidism","volume":"152","author":"Jin","year":"2012","journal-title":"Surgery"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.surg.2015.09.006","article-title":"Expanding the net: The re-evaluation of the multidimensional nomogram calculating the upper limit of normal PTH (maxPTH) in the setting of secondary hyperparathyroidism and the development of the MultIdimensional Predictive hyperparaTHyroid model (Mi-PTH)","volume":"159","author":"Rajhbeharrysingh","year":"2016","journal-title":"Surgery"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e10391","DOI":"10.1002\/jbm4.10391","article-title":"Normocalcemic Hyperparathyroidism: A Heterogeneous Disorder Often Misdiagnosed?","volume":"4","author":"Zavatta","year":"2020","journal-title":"JBMR Plus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e078378","DOI":"10.1136\/bmj-2023-078378","article-title":"TRIPOD+AI statement: Updated guidance for reporting clinical prediction models that use regression or machine learning methods","volume":"385","author":"Collins","year":"2024","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1067\/msy.2000.107066","article-title":"Technetium 99m-MIBI-SPECT: A highly sensitive diagnostic tool for localization of parathyroid adenomas","volume":"128","author":"Moka","year":"2000","journal-title":"Surgery"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"584","DOI":"10.2967\/jnumed.119.233213","article-title":"Preoperative Localization of Adenomas in Primary Hyperparathyroidism: The Value of 11C-Choline PET\/CT in Patients with Negative or Discordant Findings on Ultrasonography and 99mTc-Sestamibi SPECT\/CT","volume":"61","author":"Liu","year":"2020","journal-title":"J. Nucl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1007\/s00259-018-4123-z","article-title":"Diagnostic performance of choline PET for detection of hyperfunctioning parathyroid glands in hyperparathyroidism: A systematic review and meta-analysis","volume":"46","author":"Treglia","year":"2019","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_22","unstructured":"(2024). Reference Intervals for Common Clinical Biochemistry Tests (Standard No. WS\/T 403-2024)."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"b2393","DOI":"10.1136\/bmj.b2393","article-title":"Multiple imputation for missing data in epidemiological and clinical research: Potential and pitfalls","volume":"338","author":"Sterne","year":"2009","journal-title":"BMJ"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.jclinepi.2015.04.005","article-title":"Prediction models need appropriate internal, internal-external, and external validation","volume":"69","author":"Steyerberg","year":"2016","journal-title":"J. Clin. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Van Calster, B., McLernon, D.J., van Smeden, M., Wynants, L., and Steyerberg, E.W. (2019). Topic Group \u2018Evaluating diagnostic tests and prediction models\u2019 of the STRATOS initiative. Calibration: The Achilles heel of predictive analytics. BMC Med., 17.","DOI":"10.1186\/s12916-019-1466-7"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1177\/0272989X06295361","article-title":"Decision curve analysis: A novel method for evaluating prediction models","volume":"26","author":"Vickers","year":"2006","journal-title":"Med. Decis. Mak."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.eprac.2023.12.004","article-title":"The Ca\u2217Cl\/P Ratio: A Novel and More Appropriate Screening Tool for Normocalcaemic or Overt Primary Hyperparathyroidism","volume":"30","author":"Yu","year":"2024","journal-title":"Endocr. Pract."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1007\/s40618-023-02260-8","article-title":"Calcium\/phosphate ratio: An additional tool for the clinical management of asymptomatic primary hyperparathyroidism?","volume":"47","author":"Castellano","year":"2024","journal-title":"J. Endocrinol. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/cen.70052","article-title":"Biochemical Ratios for Predicting Primary Hyperparathyroidism: Revisiting Simple yet Powerful Diagnostic Tools","volume":"104","author":"Demir","year":"2026","journal-title":"Clin. Endocrinol. Oxf."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1007\/s00330-024-11159-8","article-title":"Machine learning-derived clinical decision algorithm for the diagnosis of hyperfunctioning parathyroid glands in patients with primary hyperparathyroidism","volume":"35","author":"Yeh","year":"2025","journal-title":"Eur. Radiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.surg.2016.09.044","article-title":"Improving diagnostic recognition of primary hyperparathyroidism with machine learning","volume":"161","author":"Somnay","year":"2017","journal-title":"Surgery"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jss.2017.05.117","article-title":"Machine learning to identify multigland disease in primary hyperparathyroidism","volume":"219","author":"Imbus","year":"2017","journal-title":"J. Surg. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1002\/hed.26970","article-title":"Machine learning can identify patients at risk of hyperparathyroidism without known calcium and intact parathyroid hormone","volume":"44","author":"Greer","year":"2022","journal-title":"Head Neck"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e783","DOI":"10.1210\/clinem\/dgae239","article-title":"Evaluation of the thiazide challenge test to differentiate primary from hypercalciuria-related hyperparathyroidism","volume":"110","author":"Verly","year":"2025","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"52","DOI":"10.14341\/probl13150","article-title":"The short test with hydrochlorothiazide in differential diagnosis between primary normocalcemic and secondary hyperparathyroidism for inpatient treatment","volume":"68","author":"Eremkina","year":"2022","journal-title":"Probl. Endokrinol. Mosk"},{"key":"ref_36","first-page":"EP184","article-title":"The short test with active metabolites of vitamin D in differential diagnosis between primary normocalcemic and secondary hyperparathyroidism for inpatient treatment","volume":"81","author":"Karaseva","year":"2022","journal-title":"Endocr. Abstr."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/19\/3200\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:24:47Z","timestamp":1790929487000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/19\/3200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":36,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["diagnostics16193200"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16193200","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,2]]}}}