Enhanced interpretation of newborn screening results without analyte cutoff values

Gregg Marquardt, 1; Currier, Robert; Phd, 2; McHugh 1, David M. S.; Gavrilov, Dimitar; Md,; Phd, 1; Magera 1, Mark J.; Matern, Dietrich; 1, Md; Oglesbee, Devin; Phd, 1; Raymond, Kimiyo; 1, Md; Rinaldo, Piero; Md,; Phd, 1; Smith, Emily H.; Phd, 1; Tortorelli, Silvia; Md,; Phd, 1; Turgeon 1, Coleman T.; Lorey, Fred; Phd, 2; Wilcken, Bridget; 3, Md; Wiley, Veronica; Phd, 3; Greed, Lawrence C.; Bsc, 4; Lewis, Barry; 4, Md; Boemer, François; PharmD PhD, 5; Schoos, Roland; Phd, 5; Marie, Sandrine; Phd, 6; Marie Françoise Vincent,; Md,; Phd, 6; Yuri Cleverthon Sica,; Msc, 7; Mouseline Torquado Domingos, 7; Khalid Al Thihli,; 8, Md; Sinclair, Graham; Phd, 8; Al Dirbashi, Osama Y.; Phd, 9; Chakraborty, Pranesh; 9, Md; Mark Dymerski 10,; Cory Porter 10,; Manning, Adrienne; 11,; Seashore, Margretta R.; 12, Md; Quesada, Jonessy; 13, Md; Alejandra Reuben 13,; Chrastina, Petr; Msc, 14; Hornik, Petr; Phd, 14; Iman Atef Mandour,; 15, Md; Sahar Abdel Atty Sharaf,; 15, Md; Bodamer, Olaf; Md,; Phd, 16; Bonifacio, Dy; 17, Md; Jasmin Torres 17,; Zori, Roberto; 18, Md; Cheillan, David; Phd, 19; Christine Vianey Saban,; Phd, 19; David Ludvigson 20,; Adrya Stembridge 21,; Bonham, Jim; Phd, 22; Downing, Melanie; Msc, 22; Dotsikas, Yannis; Phd, 23; Loukas, Yannis L.; Phd, 23; Papakonstantinou, Vagelis; Phd, 24; Zacharioudakis, Georgios S. A.; Phd, 24; Baráth, Ákos; Phd, 25; Karg, Eszter; Md,; Phd, 25; Franzson, Leifur; Phd, 26; Jonsson, Jon J.; Md,; Phd, 26; Breen 27, Nancy N.; Lesko 27, Barbara G.; Berberich, Stanton L.; Phd, 28; Turner, Kimberley; 29, Rn; Ruoppolo, Margherita; 30, Md; Emanuela Scolamiero 30,; Antonozzi, Italo; 31, Md; Carducci, Claudia; 31, Ms; Ubaldo Caruso 32,; Michela Cassanello 32,; Giancarlo la Marca,; Pharm Sc 33,; Pasquini, Elisabetta; 34, Md; Iole Maria Di Gangi,; Phd, 35; Giordano, Giuseppe; Phd, 35; Camilot, Marta; Phd, 36; Francesca Teofoli 36,; Manos, Shawn M.; 37, Bs; Peterson, Colleen K.; 37, Bs; Mayfield Gibson, Stephanie K.; 38, Md; Sevier 38, Darrin W.; Soo Youn Lee,; Md,; Phd, 39; Hyung2 Doo Park,; Md,; Phd, 39; Khneisser, Issam; 40, Ms; Phaidra Browning 41,; Fizza Gulamali Majid,; Phd, 42; Watson, Michael S.; Phd, 43; Eaton, Roger B.; Phd, 44; Sahai, Inderneel; 44, Md; Consuelo Ruiz 45,; Rosario Torres 45,; Seeterlin, Mary A.; Phd, 46; Stanley 46, Eleanor L.; Amy Hietala 47,; Mark McCann 47,; Carlene Campbell 48,; Hopkins 48, Patrick V.; de Sain Van der Velden, Monique G.; Phd, 49; Bert Elvers 50,; Morrissey, Mark A.; Phd, 51; Sherlykutty Sunny 51,; Knoll, Detlef; Msc, 52; Webster, Dianne; Phd, 52; Frazier, Dianne M.; Phd, 53; Mcclure, Julie D.; Mph, 53; Sesser 54, David E.; Willis 54, Sharon A.; Rocha, Hugo; Msc, 55; Vilarinho, Laura; Phd, 55; John, Catharine; Phd, 56; Lim, James; Phd, 56; Graham Caldwell 57, S.; Tomashitis, Kathy; Mns, 57; Castiñeiras Ramos 58, Daisy E.; Jose Angel Cocho de Juan,; Phd, 58; Inmaculada Rueda Fernández,; 59, Md; Raquel Yahyaoui Macías,; 59, Md; José María Egea Mellado 60,; Inmaculada González Gallego,; Phd, 60; Carmen Delgado Pecellin,; Phd, 61; Maria Sierra García Valdecasas Bermejo,; Phd, 61; Yin Hsiu Chien,; Md,; Phd, 62; Wuh Liang Hwu,; Md,; Phd, 62; Childs, Thomas; 63, Mt; McKeever 63, Christine D.; Tanyalcin, Tijen; Md,; Phd, 64; Abdulrahman, Mahera; Md,; Phd, 65; Queijo, Cecilia; Phd, 66; Lemes, Aída; 66, Md; Tim Davis 67,; William Hoffman 67,; Baker, Mei; 68, Md; Gary, L. Hoffman 6. 8.

doi:10.1038/gim.2012.2.

A collaboration among 157 newborn screening programs in 47 countries has lead to the creation of a database of 705,333 discrete analyte concentrations from 11,462 cases affected with 57 metabolic disorders, and from 631 heterozygotes for 12 conditions. This evidence was first applied to establish disease ranges for amino acids and acylcarnitines, and clinically validate 114 cutoff target ranges. Objective: To improve quality and performance with an evidence-based approach, multivariate pattern recognition software has been developed to aid in the interpretation of complex analyte profiles. The software generates tools that convert multiple clinically significant results into a single numerical score based on overlap between normal and disease ranges, penetration within the disease range, differences between specific conditions, and weighted correction factors. Design: Eighty-five on-line tools target either a single condition or the differential diagnosis between two or more conditions. Scores are expressed as a numerical value and as the percentile rank among all cases with the condition chosen as primary target, and are compared to interpretation guidelines. Tools are updated automatically after any new data submission (2009- 2011: 5.2 new cases added per day on average). Main outcome measures: Retrospective evaluation of past cases suggest that these tools could have avoided at least half of 277 false positive outcomes caused by carrier status for fatty acid oxidation disorders, and could have prevented 88% of false negative events caused by cutoff 7 values set inappropriately. In Minnesota, their prospective application has been a major contributing factor to the sustained achievement of a false positive rate below 0.1% and a positive predictive value above 60%. Conclusions: Application of this computational approach to raw data could make cutoff values for single analytes effectively obsolete. This paradigm is not limited to newborn screening and is applicable to the interpretation of diverse multi-analyte profiles utilized in laboratory medicine. Abstract word

Enhanced interpretation of newborn screening results without analyte cutoff values / Gregg Marquardt, 1; Robert, Currier; Phd, 2; David M. S., McHugh 1; Dimitar, Gavrilov; Md, ; Phd, 1; Mark J., Magera 1; Dietrich, Matern; Md, 1; Devin, Oglesbee; Phd, 1; Kimiyo, Raymond; Md, 1; Piero, Rinaldo; Md, ; Phd, 1; Emily H., Smith; Phd, 1; Silvia, Tortorelli; Md, ; Phd, 1; Coleman T., Turgeon 1; Fred, Lorey; Phd, 2; Bridget, Wilcken; Md, 3; Veronica, Wiley; Phd, 3; Lawrence C., Greed; Bsc, 4; Barry, Lewis; Md, 4; François, Boemer; PharmD PhD, 5; Roland, Schoos; Phd, 5; Sandrine, Marie; Phd, 6; Marie Françoise, Vincent; Md, ; Phd, 6; Yuri Cleverthon, Sica; Msc, 7; Mouseline Torquado Domingos, 7; Khalid Al, Thihli; Md, 8; Graham, Sinclair; Phd, 8; Osama Y., Al Dirbashi; Phd, 9; Pranesh, Chakraborty; Md, 9; Mark Dymerski, 10; Cory Porter, 10; Adrienne, Manning; 11, ; Margretta R., Seashore; Md, 12; Jonessy, Quesada; Md, 13; Alejandra Reuben, 13; Petr, Chrastina; Msc, 14; Petr, Hornik; Phd, 14; Iman Atef, Mandour; Md, 15; Sahar Abdel Atty, Sharaf; Md, 15; Olaf, Bodamer; Md, ; Phd, 16; Bonifacio, Dy; Md, 17; Jasmin Torres, 17; Roberto, Zori; Md, 18; David, Cheillan; Phd, 19; Christine Vianey, Saban; Phd, 19; David Ludvigson, 20; Adrya Stembridge, 21; Jim, Bonham; Phd, 22; Melanie, Downing; Msc, 22; Yannis, Dotsikas; Phd, 23; Yannis L., Loukas; Phd, 23; Vagelis, Papakonstantinou; Phd, 24; Georgios S. A., Zacharioudakis; Phd, 24; Ákos, Baráth; Phd, 25; Eszter, Karg; Md, ; Phd, 25; Leifur, Franzson; Phd, 26; Jon J., Jonsson; Md, ; Phd, 26; Nancy N., Breen 27; Barbara G., Lesko 27; Stanton L., Berberich; Phd, 28; Kimberley, Turner; Rn, 29; Ruoppolo, Margherita; Md, 30; Emanuela Scolamiero, 30; Italo, Antonozzi; Md, 31; Claudia, Carducci; Ms, 31; Ubaldo Caruso, 32; Michela Cassanello, 32; Giancarlo la, Marca; Pharm Sc, 33; Elisabetta, Pasquini; Md, 34; Iole Maria Di, Gangi; Phd, 35; Giuseppe, Giordano; Phd, 35; Marta, Camilot; Phd, 36; Francesca Teofoli, 36; Shawn M., Manos; Bs, 37; Colleen K., Peterson; Bs, 37; Stephanie K., Mayfield Gibson; Md, 38; Darrin W., Sevier 38; Soo Youn, Lee; Md, ; Phd, 39; Hyung2 Doo, Park; Md, ; Phd, 39; Issam, Khneisser; Ms, 40; Phaidra Browning, 41; Fizza Gulamali, Majid; Phd, 42; Michael S., Watson; Phd, 43; Roger B., Eaton; Phd, 44; Inderneel, Sahai; Md, 44; Consuelo Ruiz, 45; Rosario Torres, 45; Mary A., Seeterlin; Phd, 46; Eleanor L., Stanley 46; Amy Hietala, 47; Mark McCann, 47; Carlene Campbell, 48; Patrick V., Hopkins 48; Monique G., de Sain Van der Velden; Phd, 49; Bert Elvers, 50; Mark A., Morrissey; Phd, 51; Sherlykutty Sunny, 51; Detlef, Knoll; Msc, 52; Dianne, Webster; Phd, 52; Dianne M., Frazier; Phd, 53; Julie D., Mcclure; Mph, 53; David E., Sesser 54; Sharon A., Willis 54; Hugo, Rocha; Msc, 55; Laura, Vilarinho; Phd, 55; Catharine, John; Phd, 56; James, Lim; Phd, 56; S., Graham Caldwell 57; Kathy, Tomashitis; Mns, 57; Daisy E., Castiñeiras Ramos 58; Jose Angel Cocho de, Juan; Phd, 58; Inmaculada Rueda, Fernández; Md, 59; Raquel Yahyaoui, Macías; Md, 59; José María Egea Mellado, 60; Inmaculada González, Gallego; Phd, 60; Carmen Delgado, Pecellin; Phd, 61; Maria Sierra García Valdecasas, Bermejo; Phd, 61; Yin Hsiu, Chien; Md, ; Phd, 62; Wuh Liang, Hwu; Md, ; Phd, 62; Thomas, Childs; Mt, 63; Christine D., McKeever 63; Tijen, Tanyalcin; Md, ; Phd, 64; Mahera, Abdulrahman; Md, ; Phd, 65; Cecilia, Queijo; Phd, 66; Aída, Lemes; Md, 66; Tim Davis, 67; William Hoffman, 67; Mei, Baker; Md, 68; Gary, L. Hoffman 6. 8.. - In: GENETICS IN MEDICINE. - ISSN 1098-3600. - 10:(2012), pp. 20-30. [10.1038/gim.2012.2.]