Enhanced interpretation of newborn screening results without analyte cutoff values

Gregg Marquardt, Robert Currier, David M.S. McHugh, Dimitar Gavrilov, Mark J. Magera, Dietrich Matern, Devin Oglesbee, Kimiyo Raymond, Piero Rinaldo*, Emily H. Smith, Silvia Tortorelli, Coleman T. Turgeon, Fred Lorey, Bridget Wilcken, Veronica Wiley, Lawrence C. Greed, Barry Lewis, François Boemer, Roland Schoos, Sandrine MarieMarie Françoise Vincent, Yuri Cleverthon Sica, Mouseline Torquado Domingos, Khalid Al-Thihli, Graham Sinclair, Osama Y. Al-Dirbashi, Pranesh Chakraborty, Mark Dymerski, Cory Porter, Adrienne Manning, Margretta R. Seashore, Jonessy Quesada, Alejandra Reuben, Petr Chrastina, Petr Hornik, Iman Atef Mandour, Sahar Abdel Atty Sharaf, Olaf Bodamer, Bonifacio Dy, Jasmin Torres, Roberto Zori, David Cheillan, Christine Vianey-Saban, David Ludvigson, Adrya Stembridge, Jim Bonham, Melanie Downing, Yannis Dotsikas, Yannis L. Loukas, Vagelis Papakonstantinou, Georgios S.A. Zacharioudakis, Kos Baráth, Eszter Karg, Leifur Franzson, Jon J. Jonsson, Nancy N. Breen, Barbara G. Lesko, Stanton L. Berberich, Kimberley Turner, Margherita Ruoppolo, Emanuela Scolamiero, Italo Antonozzi, Claudia Carducci, Ubaldo Caruso, Michela Cassanello, Giancarlo La Marca, Elisabetta Pasquini, Iole Maria Di Gangi, Giuseppe Giordano, Marta Camilot, Francesca Teofoli, Shawn M. Manos, Colleen K. Peterson, Stephanie K. Mayfield Gibson, Darrin W. Sevier, Soo Youn Lee, Hyung Doo Park, Issam Khneisser, Phaidra Browning, Fizza Gulamali-Majid, Michael S. Watson, Roger B. Eaton, Inderneel Sahai, Consuelo Ruiz, Rosario Torres, Mary A. Seeterlin, Eleanor L. Stanley, Amy Hietala, Mark McCann, Carlene Campbell, Patrick V. Hopkins, Monique G. De Sain-Van Der Velden, Bert Elvers, Mark A. Morrissey, Sherlykutty Sunny, Detlef Knoll, Dianne Webster, Dianne M. Frazier, Julie D. McClure, David E. Sesser, Sharon A. Willis, Hugo Rocha, Laura Vilarinho, Catharine John, James Lim, S. Graham Caldwell, Kathy Tomashitis, Daisy E. Castĩeiras Ramos, Jose Angel Cocho De Juan, Inmaculada Rueda Fernández, Raquel Yahyaoui MacÍas, José María Egea-Mellado, Inmaculada González-Gallego, Carmen Delgado Pecellin, Maria Sierra García-Valdecasas Bermejo, Yin Hsiu Chien, Wuh Liang Hwu, Thomas Childs, Christine D. McKeever, Tijen Tanyalcin, Mahera Abdulrahman, Cecilia Queijo, Aída Lemes, Tim Davis, William Hoffman, Baker Mei, Gary L. Hoffman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

107 Citations (Scopus)


Purpose: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. Methods: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. Results: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. Conclusion: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.

Original languageEnglish
Pages (from-to)648-655
Number of pages8
JournalGenetics in Medicine
Issue number7
Publication statusPublished - Jul 2012
Externally publishedYes


  • cutoff values
  • false-positive rate
  • inborn errors of metabolism
  • newborn screening
  • positive predictive value

ASJC Scopus subject areas

  • Genetics(clinical)


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