{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:23:12Z","timestamp":1785424992006,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Office, Jordanian Ministry of Higher Education","award":["2014-12-24-7"],"award-info":[{"award-number":["2014-12-24-7"]}]},{"DOI":"10.13039\/501100002724","name":"American University of Sharjah","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002724","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/001g2fj96","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Purpose: This study introduces a robust approach for establishing reference intervals (RIs) for thyroid biomarkers in the Jordanian population by incorporating symptoms-based criteria into the control group selection. This method enhances the traditional inclusion\u2013exclusion criteria by adding a symptom layer. Five thyroid biomarkers were analyzed: thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid receptor antibodies (TRAbs), and antithyroid peroxidase antibodies (TPOAb). The study also investigated the prevalence of thyroid disorders using the established population-specific RIs. Patients and Methods: Samples from 6782 participants across different regions were collected between June 2016 and May 2017. The Kruskal\u2013Wallis and the Mann\u2013Whitney tests identified the best partitioning based on age\u2013gender significant differences, and 2.5th\u201397.5th percentiles were used to establish the RIs. Results: The TSH, FT4, and FT3 differed significantly among males and females, while no significant differences were found among different age groups. The RIs for males were as follows: TSH, 0.50\u20134.18 mIU\/L; FT4, 12.00\u201321.16 pmol\/L; and FT3, 2.28\u20134.17 pmol\/L, while the corresponding RIs for females were as follows: TSH, 0.57\u20134.61 mIU\/L; FT4, 12.02\u201324.69 pmol\/L; and FT3, 2.53\u20133.71 pmol\/L. TRAbs and TPOAb RIs were 0.3\u20131.89 IU\/L and 0.83\u201323.87 IU\/mL, respectively. The prevalence of overt hypothyroidism was 10.63%, subclinical hypothyroidism was 3.53%, overt hyperthyroidism was 0.66%, and subclinical hyperthyroidism was 1.52%. Conclusions: This study emphasizes the role of population-specific RIs in minimizing diagnostic errors. The addition of symptom criteria improved control group identification and RI accuracy. These findings improve the diagnosis of thyroid disorders in Jordan and suggest a reproducible framework for worldwide application.<\/jats:p>","DOI":"10.3390\/medsci14030362","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:01:17Z","timestamp":1782813677000},"page":"362","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Robust Control Group Identification Approach for Reference Intervals of Thyroid Biomarkers: The Case of Jordan"],"prefix":"10.3390","volume":"14","author":[{"given":"Areej","family":"Mohammed","sequence":"first","affiliation":[{"name":"Department of Industrial Engineering, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-9861","authenticated-orcid":false,"given":"Hussam","family":"Alshraideh","sequence":"additional","affiliation":[{"name":"Advanced Biosciences and Bioengineering Research Center, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates"},{"name":"Industrial Engineering Department, Jordan University of Science and Technology, Irbid P.O. Box 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munir","family":"Abu-Helalah","sequence":"additional","affiliation":[{"name":"Department of Family and Community Medicine, School of Medicine, University of Jordan, Amman P.O. Box 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-7052","authenticated-orcid":false,"given":"Abdulrahim","family":"Shamayleh","sequence":"additional","affiliation":[{"name":"Department of Industrial Engineering, American University of Sharjah, Sharjah P.O. Box 26666, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Babi\u0107 Leko, M., Gunja\u010da, I., Plei\u0107, N., and Zemunik, T. (2021). Environmental Factors Affecting Thyroid-Stimulating Hormone and Thyroid Hormone Levels. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126521"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Biondi, B., and Duntas, L.H. (2019). Subclinical hypothyroidism. The Thyroid and Its Diseases: A Comprehensive Guide for the Clinician, Springer.","DOI":"10.1007\/978-3-319-72102-6_18"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1080\/1744666X.2020.1811089","article-title":"The prevalence of thyroid autoantibodies in autoimmune connective tissue diseases: A systematic review and meta-analysis","volume":"16","author":"Wang","year":"2020","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/agm2.12165","article-title":"Expert consensus on diagnosis and treatment for elderly with thyroid diseases in China (2021)","volume":"4","author":"Liu","year":"2021","journal-title":"Aging Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e22344","DOI":"10.1002\/jcla.22344","article-title":"Reference intervals of trimester-specific thyroid stimulating hormone and free thyroxine in Chinese women established by experimental and statistical methods","volume":"32","author":"Han","year":"2018","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S2213-8587(18)30371-1","article-title":"Reference intervals in the diagnosis of thyroid dysfunction: Treating patients not numbers","volume":"7","author":"Jonklaas","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e23197","DOI":"10.1002\/jcla.23197","article-title":"Reference intervals for thyroid-stimulating hormone and thyroid hormones using the access TSH 3rd IS method in China","volume":"34","author":"Li","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1055\/a-2014-4589","article-title":"Control of Thyroid Dysfunction in Spanish Population Registered in the Primary Care Clinical Database: An Analysis of the Proportion of Patients with Thyrotropin Values Outside the Reference Range","volume":"55","author":"Iglesias","year":"2023","journal-title":"Horm. Metab. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1089\/thy.2022.0567","article-title":"The Impact of Age- and Sex-Specific Reference Ranges for Serum Thyrotropin and Free Thyroxine on the Diagnosis of Subclinical Thyroid Dysfunction: A Multicenter Study from Japan","volume":"33","author":"Yamada","year":"2023","journal-title":"Thyroid"},{"key":"ref_10","unstructured":"(2010). Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory. Approved Guidelines (Standard No. CLSI C28-A3)."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1515\/labmed-2020-0131","article-title":"Review of potentials and limitations of indirect approaches for estimating reference limits\/intervals of quantitative procedures in laboratory medicine","volume":"45","author":"Haeckel","year":"2021","journal-title":"J. Lab. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1089\/thy.2018.0579","article-title":"A Cross-Sectional Study to Assess the Prevalence of Adult Thyroid Dysfunction Disorders in Jordan","volume":"29","author":"Alshraideh","year":"2019","journal-title":"Thyroid"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"204","DOI":"10.2478\/enr-2021-0022","article-title":"Transient high thyroid stimulating hormone and hypothyroidism incidence during follow up of subclinical hypothyroidism","volume":"55","author":"Alshraideh","year":"2021","journal-title":"Endocr. Regul."},{"key":"ref_14","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases (2026, April 14). Thyroid Tests, Available online: https:\/\/www.niddk.nih.gov\/health-information\/diagnostic-tests\/thyroid."},{"key":"ref_15","unstructured":"Rossum, G.V. (2024, July 27). Python Programming Language. Available online: https:\/\/www.python.org\/."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1258\/jms.2010.010057","article-title":"A randomized double-blind crossover trial to investigate the efficacy of screening for adult hypothyroidism","volume":"17","author":"Law","year":"2010","journal-title":"J. Med. Screen."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/s41588-018-0058-3","article-title":"Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes","volume":"50","author":"Malik","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3803\/EnM.2023.1638","article-title":"Thyroid Hormone Reference Intervals among Healthy Individuals In Lanzhou, China","volume":"38","author":"Lu","year":"2023","journal-title":"Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1007\/s12011-020-02083-1","article-title":"Trend of Iodine Status in the Eastern Mediterranean Region and Impact of the Universal Salt Iodization Programs: A Narrative Review","volume":"198","author":"Doggui","year":"2020","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1089\/105072501300176462","article-title":"Iodine-Induced Hypothyroidism","volume":"11","author":"Markou","year":"2001","journal-title":"Thyroid"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1177\/00045632221077865","article-title":"Reference intervals for thyroid-stimulating hormone, free thyroxine, free triiodothyronine, and total triiodothyronine in the Lebanese adult population","volume":"59","author":"Salameh","year":"2022","journal-title":"Ann. Clin. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"488","DOI":"10.17344\/acsi.2020.5922","article-title":"First Estimation of Reference Intervals for Thyroid-Stimulating Hormone and Thyroid Hormones in Slovenian Population","volume":"68","author":"Oblak","year":"2021","journal-title":"Acta Chim. Slov."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Xie, T., Su, M., Feng, J., Pan, X., Wang, C., and Tang, T. (2023). The reference intervals for thyroid hormones: A four year investigation in Chinese population. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1046381"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.cccn.2005.07.003","article-title":"Thyroid hormone reference intervals in an ambulatory Arab population on the Abbott Architect i2000 immunoassay analyzer","volume":"364","author":"Dhatt","year":"2006","journal-title":"Clin. Chim. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1177\/2042018818781299","article-title":"Reference intervals of thyroid hormones in a previously iodine-deficient area in Darfur, Sudan","volume":"9","author":"Ali","year":"2018","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Musa, I.R., Ali, N.I., Elseed, S.A., Osman, O.E., and Adam, I. (2018). Reference intervals of thyroid hormones in Khartoum, Sudan. BMC Res. Notes, 11.","DOI":"10.1186\/s13104-018-3840-5"},{"key":"ref_27","first-page":"e2021283","article-title":"Thyroid stimulating hormone reference range: Iranian thyroid cohort study","volume":"92","author":"Meamar","year":"2021","journal-title":"Acta Biomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1089\/thy.2015.0276","article-title":"Sex- and Age-Specific Reference Values and Cutoff Points for TPOAb: Tehran Thyroid Study","volume":"26","author":"Amouzegar","year":"2016","journal-title":"Thyroid"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1017\/S0007114522002367","article-title":"Relationships between the serum TPOAb and TGAb antibody distributions and water iodine concentrations, thyroid hormones and thyroid diseases: A cross-sectional study of 2503 adults in China","volume":"129","author":"He","year":"2023","journal-title":"Br. J. Nutr."},{"key":"ref_30","first-page":"665","article-title":"Thyroid hormone reference intervals and the prevalence of thyroid antibodies","volume":"40","author":"Bilgili","year":"2010","journal-title":"Turk. J. Med. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/bmb\/ldr030","article-title":"The epidemiology of thyroid disease","volume":"99","author":"Vanderpump","year":"2011","journal-title":"Br. Med. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zou, S., Wu, F., Guo, C., Song, J., Huang, C., Zhu, Z., Yu, H., Guo, Y., Lu, X., and Ruan, Y. (2012). Iodine nutrition and the prevalence of thyroid disease after salt iodization: A cross-sectional survey in Shanghai, a coastal area in China. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040718"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1507\/endocrj.EJ15-0574","article-title":"Reference intervals of thyroid hormones in a previously iodine-deficient but presently more than adequate area of Western China: A population-based survey","volume":"63","author":"Cai","year":"2016","journal-title":"Endocr. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/cen.14454","article-title":"Factors influencing the reference interval of thyroid-stimulating hormone in healthy adults: A systematic review and meta-analysis","volume":"95","author":"Xing","year":"2021","journal-title":"Clin. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.beem.2009.08.013","article-title":"Iodine intake as a determinant of thyroid disorders in populations","volume":"24","author":"Laurberg","year":"2010","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4270","DOI":"10.1210\/jc.2016-2255","article-title":"Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis","volume":"101","author":"Chaker","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1507\/endocrj.K11E-101","article-title":"An epidemiological study of the serum thyrotropin reference range and factors that influence serum thyrotropin levels in iodine sufficient areas of China","volume":"58","author":"Li","year":"2011","journal-title":"Endocr. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nrendo.2018.18","article-title":"Global epidemiology of hyperthyroidism and hypothyroidism","volume":"14","author":"Taylor","year":"2018","journal-title":"Nat. Rev. Endocrinol."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/3\/362\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:39:53Z","timestamp":1783053593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/3\/362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":38,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["medsci14030362"],"URL":"https:\/\/doi.org\/10.3390\/medsci14030362","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}