Application of principal component analysis to newborn screening for congenital adrenal hyperplasia
Open accessAbstract
PURPOSE: Newborn screening laboratories are challenged to develop reporting algorithms that accurately identify babies at increased risk for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). Screening algorithms typically use cutoff values for a key steroid(s) and include considerations for covariates, such as gestational age or birth weight, but false-positive and false-negative results are still too frequent, preventing accurate assessments. Principal component analysis (PCA) is a statistical method that reduces high-dimensional data to a small number of components, capturing patterns of association that may be relevant to the outcome of interest. To our knowledge, PCA has not been evaluated in the newborn screening setting to determine whether it can improve the positive predictive value of 21OHD screening. METHODS: PCA was applied to a data set of 920 newborns with measured concentrations of 5 key steroids that are known to be perturbed in patients with 21OHD. A decision tree for the known outcomes (confirmed 21OHD cases and unaffected individuals) was created with 2 principal components as predictors. The effectiveness of the PCA-derived decision tree was compared with the current algorithm. RESULTS: PCA improved the positive predictive value of 21OHD screening from 20.0% to 66.7% in a retrospective study comparing the current algorithm to a tree-based algorithm using PCA-derived variables. The streamlined PCA-derived decision tree, comprising only 3 assessment points, greatly simplified the 21OHD reporting algorithm. CONCLUSIONS: This first report of PCA applied to newborn screening for 21OHD demonstrates enhanced detection of affected individuals within the unaffected population.
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Some but not all laboratories have reported markedly superior results with steroid ratios, with one recent report claiming a positive predictive value of 71%.
“Some (272,273) but not all (254) laboratories have reported markedly superior results with these approaches, with one recent report claiming a positive predictive value of 71% (270).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [272]
The cited paper reports a positive predictive value of 66.7% for its PCA-derived decision tree, not 71% (Distribution of PC6; page unavailable). It reports 20% for the existing screening algorithm. The 71% figure is the part of the citing sentence attributed to this paper. (LLM, conf=0.88)
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Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,706 · see citing works
Applied Multivariate Statistical Analysis.
Johnson, A., & Wichern, D. W. (1988) · Biometrics · doi:10.2307/2531616 · Cited by 11,374 · see citing works
Bro, R., & Smilde, A. K. (2014) · Anal. Methods · doi:10.1039/c3ay41907j · Cited by 3,038 · see citing works
Classification and regression trees
Loh, W. (2011) · Wiley Interdisciplinary Reviews Data Mining and Knowledge Discovery · doi:10.1002/widm.8 · Cited by 2,464 · see citing works
Lever, J., Krzywinski, M. I., & Altman, N. (2017) · Nature Methods · doi:10.1038/nmeth.4346 · Cited by 1,468 · see citing works
Congenital Adrenal Hyperplasia
Speiser, P., & White, P. C. (1987) · New England Journal of Medicine · doi:10.1056/nejm198711263172211 · Cited by 1,409 · see citing works
Speiser, P. W., Arlt, W., Auchus, R. J., Baskin, L. S., Conway, G. S., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Murad, M. H., Oberfield, S. E., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01865 · Cited by 1,234 · see citing works
rpart: Recursive Partitioning and Regression Trees
Therneau, T. M., & Atkinson, B. (1999) · doi:10.32614/cran.package.rpart · Cited by 750 · see citing works
Congenital adrenal hyperplasia
El-Maouche, D., Arlt, W., & Merke, D. P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31431-9 · Cited by 669 · see citing works
Recursive Partitioning and Regression Trees
Therneau, T. M., Atkinson, B., & Ripley, B. D. (2015) · Cited by 466 · see citing works
Therrell, B. L., Berenbaum, S. A., Manter-Kapanke, V., Simmank, J., Korman, K., Prentice, L., Gonzalez, J., & Gunn, S. (1998) · Pediatrics · doi:10.1542/peds.101.4.583 · Cited by 344 · see citing works
Vidal, R., Ma, Y., & Sastry, S. (2016) · Interdisciplinary applied mathematics · doi:10.1007/978-0-387-87811-9_2 · Cited by 337 · see citing works
Speiser, P., Arlt, W., Rj, A., Baskin, L., Conway, G. S., Merke, D. P., Meyer‐Bahlburg, H. F. L., Miller, W. L., Murad, M. H., Oberfield, S., et al. (2019) · Yearbook of pediatric endocrinology · doi:10.1530/ey.16.8.5 · Cited by 301 · see citing works
PANG, S., HOTCHKISS, J., DRASH, A. L., LEVINE, L. S., & NEW, M. I. (1977) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-45-5-1003 · Cited by 293 · see citing works
Neonatal screening for congenital adrenal hyperplasia
White, P. C. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.148 · Cited by 240 · see citing works
Lacey, J. M., Minutti, C. Z., Magera, M. J., Tauscher, A. L., Casetta, B., McCann, M., Lymp, J., Hahn, S. H., Rinaldo, P., & Matern, D. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2003.027193 · Cited by 216 · see citing works
Allen, D. B., Hoffman, G. L., Fitzpatrick, P., Laessig, R., Maby, S., & Slyper, A. (1997) · The Journal of Pediatrics · doi:10.1016/s0022-3476(97)70321-4 · Cited by 153 · see citing works
Self-citationPostanalytical tools improve performance of newborn screening by tandem mass spectrometry
Hall, P., Marquardt, G., McHugh, D. M. S., Currier, R. J., Tang, H. T., Stoway, S. D., & Rinaldo, P. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.62 · Cited by 131 · see citing works
Enhanced interpretation of newborn screening results without analyte cutoff values
Marquardt, G., Currier, R. J., McHugh, D. M. S., Gavrilov, D. K., Magera, M. J., Matern, D., Oglesbee, D., Raymond, K., Rinaldo, P., Smith, E. H., et al. (2012) · Genetics in Medicine · doi:10.1038/gim.2012.2 · Cited by 125 · see citing works
Olgemöller, B., Roscher, A. A., Liebl, B., & Fingerhut, R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021732 · Cited by 124 · see citing works
Precision newborn screening for lysosomal disorders
Baerg, M. M. M., Stoway, S. D., Hart, J., Mott, L., Peck, D. S., Nett, S. L., Eckerman, J. S., Lacey, J. M., Turgeon, C. T., Gavrilov, D. K., et al. (2017) · Genetics in Medicine · doi:10.1038/gim.2017.194 · Cited by 116 · see citing works
van der Kamp, H. J., Oudshoorn, C. G. M., Elvers, B. H., van Baarle, M., Otten, B. J., Wit, J. M., & Verkerk, P. H. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2136 · Cited by 114 · see citing works
Schwarz, E., Liu, A., Randall, H., Haslip, C., Keune, F., Murray, M., Longo, N., & Pasquali, M. (2009) · Pediatric Research · doi:10.1203/pdr.0b013e3181aa3777 · Cited by 97 · see citing works
Biochemical and genetic diagnosis of 21-hydroxylase deficiency
Falhammar, H., Wedell, A., & Nordenström, A. (2015) · Endocrine · doi:10.1007/s12020-015-0731-6 · Cited by 80 · see citing works
Comparison of one-tier and two-tier newborn screening metrics for congenital adrenal hyperplasia
Sarafoglou, K., Banks, K., Gaviglio, A., Hietala, A., McCann, M., & Thomas, W. (2012) · PEDIATRICS · doi:10.1542/peds.2012-1219 · Cited by 69 · see citing works
Puckett, R. L., Lorey, F., Rinaldo, P., Lipson, M. H., Matern, D., Sowa, M., Levine, S., Chang, R. C., Wang, R. Y., & Abdenur, J. E. (2009) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2009.11.010 · Cited by 63 · see citing works
Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota
Sarafoglou, K., Banks, K., Kyllo, J., Pittock, S., & Thomas, W. (2012) · JAMA · doi:10.1001/jama.2012.5281 · Cited by 62 · see citing works
Newborn screening for congenital adrenal hyperplasia has reduced sensitivity in girls
Varness, T. S., Allen, D. B., & Hoffman, G. L. (2005) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2005.04.035 · Cited by 61 · see citing works
Self-citationTortorelli, S., Eckerman, J. S., Orsini, J. J., Stevens, C. F., Hart, J., Hall, P., Alexander, J. J., Gavrilov, D. K., Oglesbee, D., Raymond, K., et al. (2017) · Genetics in Medicine · doi:10.1038/gim.2017.190 · Cited by 56 · see citing works
Optimizing Newborn Screening for Congenital Adrenal Hyperplasia
White, P. C. (2013) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2013.02.008 · Cited by 49 · see citing works
Mørkrid, L., Rowe, A. D., Elgstøen, K. B. P., Olesen, J. H., Ruijter, G. J. G., Hall, P., Tortorelli, S., Schulze, A., Kyriakopoulou, L. G., Wamelink, M. M. C., et al. (2015) · Clinical Chemistry · doi:10.1373/clinchem.2014.235564 · Cited by 44 · see citing works
Dhillon, K., Ho, T., Rich, P., Xu, D., Lorey, F., She, J., & Bhandal, A. (2011) · Clinica Chimica Acta · doi:10.1016/j.cca.2011.07.009 · Cited by 30 · see citing works
Bialk, E. R., Lasarev, M. R., & Held, P. K. (2019) · International Journal of Neonatal Screening · doi:10.3390/ijns5030033 · Cited by 25 · see citing works
Self-citationNegative screening tests in classical galactosaemia caused by S135L homozygosity
Crushell, E., Chukwu, J., Mayne, P., Blatný, J., & Treacy, E. P. (2009) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-009-1081-4 · Cited by 24 · see citing works
Janečková, H., Kalivodová, A., Najdekr, L., Friedecký, D., Hron, K., Bruheim, P., & Adam, T. (2014) · Biomedical Papers · doi:10.5507/bp.2014.048 · Cited by 19 · see citing works
The Need for Vigilance: The Case of a False-Negative Newborn Screen for Cystic Fibrosis
Dunn, C. T., Skrypek, M. M., Powers, A. L. R., & Laguna, T. A. (2011) · PEDIATRICS · doi:10.1542/peds.2010-0286 · Cited by 18 · see citing works
Sahai, I., Bailey, J. C., Eaton, R. B., Zytkovicz, T. H., & Harris, D. J. (2010) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2010.09.026 · Cited by 15 · see citing works
Flagged first, then by citations
1 of the 38 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
- El-Maouche D, Arlt W, Merke DD. Congenital adrenal hyper- plasia. Lancet. 2017;390:2194-2210.
- CLSI NBS03. Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns. 2nd ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2019:11-29.
- Gabler E. The price of being wrong. Milwaukee Journal Sentinel. 12 September 2016. https://projects.jsonline.com/ news/2016/12/11/the-price-of-being-wrong.html
Cited by
Sorted by citations
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Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556 · see citing works
Therrell, B. L., Padilla, C. D., Borrajo, G. J. C., Khneisser, I., Schielen, P. C. J. I., Knight‐Madden, J., Malherbe, H. L., & Kase, M. (2024) · International Journal of Neonatal Screening · doi:10.3390/ijns10020038 · Cited by 161 · see citing works
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Self-citationCurrent and Novel Treatment Strategies in Children with Congenital Adrenal Hyperplasia
Nordenström, A., Falhammar, H., & Lajić, S. (2022) · Hormone Research in Paediatrics · doi:10.1159/000522260 · Cited by 35 · see citing works
Zaunseder, E., Haupt, S., Mütze, U., Garbade, S. F., Kölker, S., & Heuveline, V. (2022) · JIMD Reports · doi:10.1002/jmd2.12285 · Cited by 31 · see citing works
Madsen, A., Bruserud, I. S., Bertelsen, B.-E., Roelants, M., Oehme, N. H. B., Viste, K., Bjerknes, R., Almås, B., Rosendahl, K., Mellgren, G., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa679 · Cited by 28 · see citing works
Ljubicic, M. L., Madsen, A., Juul, A., Almstrup, K., & Johannsen, T. H. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.652888 · Cited by 21 · see citing works
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Zaunseder, E., Mütze, U., Garbade, S. F., Haupt, S., Feyh, P., Hoffmann, G. F., Heuveline, V., & Kölker, S. (2023) · Metabolites · doi:10.3390/metabo13020304 · Cited by 19 · see citing works
Agnani, H., Bachelot, G., Eguether, T., Ribault, B., Fiet, J., Bouc, Y. L., Netchine, I., Houang, M., & Lamazière, A. (2022) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2022.106085 · Cited by 12 · see citing works
Greaves, R. F., Kumar, M., Mawad, N., Francescon, A., Le, X. C., O’Connell, M. A., Chi, J., & Pitt, J. J. (2023) · International Journal of Neonatal Screening · doi:10.3390/ijns9040058 · Cited by 12 · see citing works
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Vliet, G. V., & Grosse, S. D. (2021) · médecine/sciences · doi:10.1051/medsci/2021053 · Cited by 12 · see citing works
Ye, L., Zhao, Z., Ren, H., Wang, W., Zhou, W., Zheng, S., Zhang, J., Zhang, J., Li, H., Wan, Z., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac271 · Cited by 8 · see citing works
Yang, J., Pan, X., Luo, Y., Zhu, S., Tang, Y., Chen, H., Wang, H., Lv, F., Luo, T., Cheng, O., et al. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.02.055 · Cited by 2 · see citing works
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Wang, F., Wong, Y., Liu, H., Wu, Z., Wong, C. L. Y., Xu, D., Chan, D. K. K., Law, B., Chan, F. S., Qu, L., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2517785122 · Cited by 3 · see citing works
Scandrett, K., Dinnes, J., Morrison, B., Coombe, A., Agarwal, R., Asare, I. A., Mead, P. A., Souza, A. D., Elliman, D. A. C., Lombardo, S., et al. (2025) · Health Technology Assessment · doi:10.3310/gjjd1717 · Cited by 1 · see citing works
Honour, J. W. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-818124-9.00004-8
Zykova, S. N., Plaksienko, A., Solevåg, A. L., Brigtsen, A. K., Michelsen, T. M., Sørbye, I. K., Bentsen, M. H. L., Bakke, L. H., Elboth, J. E., Berg, J. P., et al. (2026) · Frontiers in Pediatrics · doi:10.3389/fped.2026.1808446
- Authors
- Lasarev, M. R., Bialk, E. R., Allen, D. B., & Held, P. K.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Held, Patrice K
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2020-06-11
- Volume
- 105
- Issue
- 8
- Pages
- e2930-e2940
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W3034546614
- Cited by
- 19
- References
- 38
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 2
- FWCI
- 1.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- congenital adrenal hyperplasia, 21-hydroxylase deficiency, newborn screening, principal component analysis, positive predictive value, decision tree, false positives
- MeSH terms
- Adrenal Hyperplasia, Congenital, Algorithms, Data Interpretation, Statistical, Diagnostic Techniques, Endocrine, False Positive Reactions, Female, Gestational Age, Humans, Infant, Newborn, Male, Predictive Value of Tests, Reference Values, Retrospective Studies, Steroids, Biomarkers, Neonatal Screening, Principal Component Analysis
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