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Cited by 26Thyroid Disorders and TreatmentsClinical Laboratory Practices and Quality ControlMetabolism and Genetic Disorders

A Novel Approach to Improve Newborn Screening for Congenital Hypothyroidism by Integrating Covariate-Adjusted Results of Different Tests into CLIR Customized Interpretive Tools

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Rowe, Alexander D., Stoway, Stephanie D., Åhlman, Henrik, Arora, Vaneet, Caggana, Michele, Fornari, Anna, Hagar, Arthur, Hall, Patricia L. +16 more·2021·International Journal of Neonatal Screening
DOI 10.3390/ijns7020023PMC PMC8167643
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Abstract

Newborn screening for congenital hypothyroidism remains challenging decades after broad implementation worldwide. Testing protocols are not uniform in terms of targets (TSH and/or T4) and protocols (parallel vs. sequential testing; one or two specimen collection times), and specificity (with or without collection of a second specimen) is overall poor. The purpose of this retrospective study is to investigate the potential impact of multivariate pattern recognition software (CLIR) to improve the post-analytical interpretation of screening results. Seven programs contributed reference data (N = 1,970,536) and two sets of true (TP, N = 1369 combined) and false (FP, N = 15,201) positive cases for validation and verification purposes, respectively. Data were adjusted for age at collection, birth weight, and location using polynomial regression models of the fifth degree to create three-dimensional regression surfaces. Customized Single Condition Tools and Dual Scatter Plots were created using CLIR to optimize the differential diagnosis between TP and FP cases in the validation set. Verification testing correctly identified 446/454 (98%) of the TP cases, and could have prevented 1931/5447 (35%) of the FP cases, with variable impact among locations (range 4% to 50%). CLIR tools either as made here or preferably standardized to the recommended uniform screening panel could improve performance of newborn screening for congenital hypothyroidism.

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  • Population-based reference intervals for thyroid test variables are much broader than the narrow within-subject variance and consequently are less useful for monitoring an individual patient.

    “Population-based reference intervals for thyroid test variables are, therefore, much broader than the rather narrow within-subject variance and consequently are less useful for monitoring an individual patient.108–113”

    From Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status (2023) · cites this paper as [112]

    The Results (§3.2; page unavailable) compare newborn thyroid-test reference intervals across locations and after covariate adjustment, not with within-subject variance. The Study Cohort section (§2.8; page unavailable) says repeat samples were not linked or compared within the same case. Searches for within-subject variation and individual-patient monitoring found no passage establishing the claimed comparison or its consequence. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Heritability accounts for 30% to 65% of the variance in TSH, fT4, fT3, and the fT4 × TSH product.

    “Such studies reveal that heritability accounts for 30% to 65% of the variance in TSH, fT4, fT3, and the fT4 × TSH product.”

    From Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status (2023) · cites this paper as [112]

    The Methods (section 2.7) discusses variation in TSH and T4 by age, birth weight, and location, while the Discussion (section 4) addresses newborn screening performance. Searches for heritability, the 30%–65% range, fT3, and the fT4 × TSH product found no passage addressing the claimed genetic contribution to variance. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • Systematic studies in healthy mono- and dizygotic twins, repetitive sampling studies, and testing of individuals or subpopulations in different regions have shown markedly narrower within-subject variability than between-subject variations.

    “Results from systematic studies in healthy mono- and dizygotic twins, repetitive sampling studies, and the testing of individuals or (sub-)populations in different regions have shown markedly narrower within-subject variability (e.g., during monthly sampling) than between-subject variations.”

    From Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status (2023) · cites this paper as [112]

    Section 2.7 (Adjustment Builder; page unavailable) reports variation by age, birth weight, and location, but does not compare within-subject with between-subject variability. Section 2.8 (Study Cohort; page unavailable) says repeat samples were not linked or compared. Searches for twin studies, monthly sampling, and within-subject variability found no passage supporting the claimed comparison. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Rowe, A. D., Stoway, S. D., Åhlman, H., Arora, V., Caggana, M., Fornari, A., Hagar, A., Hall, P. L., Marquardt, G. C., Miller, B. J., Nixon, C., Norgan, A. P., Orsini, J. J., Pettersen, R. D., Piazza, A. L., Schubauer, N. R., Smith, A. C., Tang, H., Tavakoli, N. P., Wei, S., Zetterström, R. H., Currier, R. J., Mørkrid, L., & Rinaldo, P.
Affiliations
  • Oslo University Hospital (NO)
  • Karolinska University Hospital (SE)
  • Kentucky Department for Public Health (US)
  • New York State Department of Health (US)
  • Mayo Clinic (US)
  • Georgia Department of Public Health (US)
  • Department of General Services (US)
  • California Department of Public Health (US)
  • University of California, San Francisco (US)
Corresponding author
Rinaldo, Piero
ORCID
Venue
International Journal of Neonatal Screening
Publisher
MDPI AG
Published
2021-04-23
Volume
7
Issue
2
Pages
23
ISSN
2409-515X (ISSN-L)
DOI
10.3390/ijns7020023
PMC
PMC8167643
OpenAlex
W3158209359
Cited by
26
References
2
Citations by year
2026: 4 · 2025: 3 · 2024: 2 · 2023: 10 · 2022: 5 · 2021: 2
FWCI
3.55
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Neonatal Screening (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
congenital hypothyroidism, newborn screening, multivariate pattern classification, screening result interpretation, false positive reduction, covariate adjustment, regression surfaces, differential diagnosis

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