{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:05:03Z","timestamp":1792512303308,"version":"4.5.0"},"reference-count":40,"publisher":"American Academy of Pediatrics (AAP)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,2,1]]},"abstract":"<jats:p>OBJECTIVES. To ensure that each newborn receives an equitable test of the highest possible sensitivity, we recognized the necessity to reassess immunoreactive trypsinogen and DNA issues in cystic fibrosis newborn screening algorithms. Our objectives included clarification of various factors that influence immunoreactive trypsinogen concentrations and resolution of long-standing questions about variations in immunoreactive trypsinogen levels among newborns.<\/jats:p><jats:p>METHODS. Immunoreactive trypsinogen data on 660443 newborns who were born between July 1, 1994, and June 30, 2004, were abstracted from the Wisconsin State Laboratory of Hygiene databases and deidentified for analysis. Using a compiled data set, we analyzed various demographic characteristics to determine their role, if any, in immunoreactive trypsinogen variation. Specifically, season of birth, reagent lot, and birth weight were examined. Sensitivities of the most common cystic fibrosis newborn screening protocols, namely immunoreactive trypsinogen\/immunoreactive trypsinogen and immunoreactive trypsinogen\/DNA, were also investigated.<\/jats:p><jats:p>RESULTS. Mean and 95th percentile immunoreactive trypsinogen levels were shown to vary by both season and reagent lot number and affect sensitivity of the assay. Low birth weight infants had significantly higher immunoreactive trypsinogen values than normal birth weight infants. Sensitivities were also found to vary on the basis of the algorithm used, with the highest sensitivity of 96.2% calculated for an immunoreactive trypsinogen\/DNA protocol with 23 cystic fibrosis transmembrane conductance regulator mutation analyses compared with 80.2% with the immunoreactive trypsinogen\/immunoreactive trypsinogen method used in 9 states.<\/jats:p><jats:p>CONCLUSIONS. Floating, rather than fixed, cutoff values for the initial immunoreactive trypsinogen portion of any cystic fibrosis newborn screening protocol are generally necessary on the basis of the seasonal and reagent lot variations observed. Because of its lower sensitivity, immunoreactive trypsinogen\/immunoreactive trypsinogen does not optimize detection of patients with cystic fibrosis.<\/jats:p>","DOI":"10.1542\/peds.2008-1681","type":"journal-article","created":{"date-parts":[[2009,1,26]],"date-time":"2009-01-26T12:23:44Z","timestamp":1232972624000},"page":"e338-e346","source":"Crossref","is-referenced-by-count":68,"title":["Clarification of Laboratory and Clinical Variables That Influence Cystic Fibrosis Newborn Screening With Initial Analysis of Immunoreactive Trypsinogen"],"prefix":"10.1542","volume":"123","author":[{"given":"Molly","family":"Kloosterboer","sequence":"first","affiliation":[{"name":"Departments of Population Health Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rock","sequence":"additional","affiliation":[{"name":"Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Gershan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Laxova","sequence":"additional","affiliation":[{"name":"Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanhai","family":"Li","sequence":"additional","affiliation":[{"name":"Biostatistics and Medical Informatics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M.","family":"Farrell","sequence":"additional","affiliation":[{"name":"Departments of Population Health Sciences"},{"name":"Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2009,2,1]]},"reference":[{"key":"2021120823002066100_R1","doi-asserted-by":"crossref","unstructured":"MacCready R. Phenylketonuria screening program. N Engl J Med.\u20081963;269(1):52\u201356","DOI":"10.1056\/NEJM196307042690117"},{"key":"2021120823002066100_R2","unstructured":"Newborn screening: toward a uniform screening panel and system. Department of Health and Human Services. Fed Regist.\u20082005;70(44): Available at: http:\/\/mchb.hrsa.gov\/screening. Accessed December 15, 2008"},{"key":"2021120823002066100_R3","doi-asserted-by":"crossref","unstructured":"Ross LF. Newborn screening for cystic fibrosis: a lesson in public health disparities. J Pediatr.\u20082008;153(3):308\u2013313","DOI":"10.1016\/j.jpeds.2008.04.061"},{"key":"2021120823002066100_R4","doi-asserted-by":"crossref","unstructured":"Crossley JR, Elliott RB, Smith PA. Dried-blood spot screening for cystic fibrosis in the newborn. Lancet.\u20081979;1:472\u2013474","DOI":"10.1016\/S0140-6736(79)90825-0"},{"key":"2021120823002066100_R5","doi-asserted-by":"crossref","unstructured":"Wilcken B, Wiley V, Sherry G, Bayliss U. Neonatal screening for cystic fibrosis: a comparison of two strategies for case detection in 1.2 million babies. J Pediatr.\u20081995;127(6):965\u2013970","DOI":"10.1016\/S0022-3476(95)70040-4"},{"key":"2021120823002066100_R6","doi-asserted-by":"crossref","unstructured":"Hammond KB, Abman SH, Sokol RJ, Accurso FJ. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. New Engl J Med.\u20081991;325(11):769\u2013774","DOI":"10.1056\/NEJM199109123251104"},{"key":"2021120823002066100_R7","doi-asserted-by":"crossref","unstructured":"Sontag MK, Hammond KB, Zielenski J, Wagener JS, Accurso FJ. Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. J Pediatr.\u20082005;147(3 Suppl):S83\u2013S88","DOI":"10.1016\/j.jpeds.2005.08.005"},{"key":"2021120823002066100_R8","doi-asserted-by":"crossref","unstructured":"Neonatal screening for cystic fibrosis: position paper. Pediatrics.\u20081983;72(5):741\u2013745","DOI":"10.1542\/peds.72.5.741"},{"key":"2021120823002066100_R9","doi-asserted-by":"crossref","unstructured":"Rock MJ, Mischler EH, Farrell PM, et al. Newborn screening for cystic fibrosis is complicated by age-related decline in immunoreactive trypsinogen levels. Pediatrics.\u20081990;85(6):1001\u20131007","DOI":"10.1542\/peds.85.6.1001"},{"key":"2021120823002066100_R10","unstructured":"Gregg RG, Wilfond BS, Farrell PM, Laxova A, Hassemer D, Mischler EH. Application of DNA analysis in a population screening program for neonatal diagnosis of cystic fibrosis: comparison of screening protocols. Am J Hum Genet.\u20081993;52(3):616\u2013626"},{"key":"2021120823002066100_R11","unstructured":"Farrell PM, Aronson RA, Hoffman G, Laessig RH. Newborn screening for cystic fibrosis in Wisconsin: first application of population-based molecular genetics testing. Wis Med J.\u20081994;93(8):415\u2013421"},{"key":"2021120823002066100_R12","doi-asserted-by":"crossref","unstructured":"Ranieri E, Lewis BD, Gerase RL, et al. Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years' experience. BMJ.\u20081994;308(6942):1469\u20131472","DOI":"10.1136\/bmj.308.6942.1469"},{"key":"2021120823002066100_R13","doi-asserted-by":"crossref","unstructured":"Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science.\u20081989;245(4922):1073\u20131080","DOI":"10.1126\/science.2570460"},{"key":"2021120823002066100_R14","doi-asserted-by":"crossref","unstructured":"Gregg RG, Simantel A, Farrell PM, et al. Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods. Pediatrics.\u20081997;99(6):819\u2013824","DOI":"10.1542\/peds.99.6.819"},{"key":"2021120823002066100_R15","doi-asserted-by":"crossref","unstructured":"Padoan R, Genoni S, Moretti E, Seia M, Giunta A, Corbetta C. Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis. Acta Paediatr.\u20082002;91(1):82\u201387","DOI":"10.1111\/j.1651-2227.2002.tb01646.x"},{"key":"2021120823002066100_R16","doi-asserted-by":"crossref","unstructured":"Farrell PM, Kosorok MR, Laxova A, et al. Nutritional benefits of newborn screening for cystic fibrosis. N Engl J Med.\u20081997;337(14):963\u2013969","DOI":"10.1056\/NEJM199710023371403"},{"key":"2021120823002066100_R17","doi-asserted-by":"crossref","unstructured":"Farrell PM, Kosorok MR, Rock MJ, Laxova A, Zeng L, Lai HC. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics.\u20082001;107(1):1\u201313","DOI":"10.1542\/peds.107.1.1"},{"key":"2021120823002066100_R18","doi-asserted-by":"crossref","unstructured":"Chatfield S, Owen G, Ryley HC. Neonatal screening for cystic fibrosis in Wales and the West Midlands: clinical assessment after 5 years of screening. Arch Dis Child.\u20081991;66(1 Spec No.):29\u201333","DOI":"10.1136\/adc.66.1_Spec_No.29"},{"key":"2021120823002066100_R19","unstructured":"Grosse SD, Boyle CA, Botkin JR, et al. Newborn screening for cystic fibrosis: evaluation of benefits and risk and recommendations for state newborn screening programs. MMWR Morb Mortal Recomm Rep.\u20082004;53(RR-13):1\u201336"},{"key":"2021120823002066100_R20","doi-asserted-by":"crossref","unstructured":"Campbell PW, White TB. Newborn screening for cystic fibrosis: an opportunity to improve care and outcomes. J Pediatr.\u20082005;147(3 Suppl):S2\u2013S5","DOI":"10.1016\/j.jpeds.2005.08.016"},{"key":"2021120823002066100_R21","doi-asserted-by":"crossref","unstructured":"Comeau AM, Accurso FJ, White TB, et al. Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report. Pediatrics.\u20082007;119(2). Available at: www.pediatrics.org\/cgi\/content\/full\/119\/2\/e495","DOI":"10.1542\/peds.2006-1993"},{"key":"2021120823002066100_R22","unstructured":"National Newborn Screening and Genetics Resource Center. National Newborn Screening Status Report. Available at: http:\/\/genes-r-us.uthscsa.edu\/nbsdisorders.pdf. Accessed December 15, 2008"},{"key":"2021120823002066100_R23","doi-asserted-by":"crossref","unstructured":"Rock MJ, Hoffman G, Laessig RH, Kopish G, Listheim T, Farrel PM. Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen\/DNA testing. J Pediatr.\u20082005;147(3 suppl):S73\u2013S77","DOI":"10.1016\/j.jpeds.2005.08.004"},{"key":"2021120823002066100_R24","doi-asserted-by":"crossref","unstructured":"Cabrini G, Pederzini F, Perobelli L, Mastella G. An evaluation of enzyme immunoassay method for immunoreactive trypsin in dried blood spots. Clin Biochem.\u20081990;23(3):213\u2013219","DOI":"10.1016\/0009-9120(90)90614-Z"},{"key":"2021120823002066100_R25","doi-asserted-by":"crossref","unstructured":"Comeau AM, Parad RB, Dorkin HL, Dovey M, Gerstle R, Haver K. Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections. Pediatrics.\u20082004;113(6):1573\u20131581","DOI":"10.1542\/peds.113.6.1573"},{"key":"2021120823002066100_R26","doi-asserted-by":"crossref","unstructured":"Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: cystic fibrosis foundation consensus report. J Pediatr.\u20082008;153(2):S4\u2013S14","DOI":"10.1016\/j.jpeds.2008.05.005"},{"key":"2021120823002066100_R27","doi-asserted-by":"crossref","unstructured":"Hemmila\u0308 I, Dakubu S, Mukkala V-M, Siltari H, Lovgren T. Europium as a label in time-resolved immunofluorometric assays. Anal Biochem.\u20081984;137(2):335\u2013343","DOI":"10.1016\/0003-2697(84)90095-2"},{"key":"2021120823002066100_R28","doi-asserted-by":"crossref","unstructured":"Farrell PM. Improving the health of patients with cystic fibrosis through newborn screening. Adv Pediatr.\u20082000;47:79\u2013115","DOI":"10.1016\/S0065-3101(23)00095-6"},{"key":"2021120823002066100_R29","unstructured":"Mischler E, Farrell P, Bruns T, et al. Neonatal screening for cystic fibrosis in Wisconsin. Wis Med J.\u20081989;88(3):14\u201317"},{"key":"2021120823002066100_R30","unstructured":"Wisconsin Department of Health and Family Services. Available at: http:\/\/dhs.wisconsin.gov\/births\/pdf\/04births.pdf. Accessed December 15, 2008"},{"key":"2021120823002066100_R31","doi-asserted-by":"crossref","unstructured":"Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med.\u20082001;3(2):149\u2013154","DOI":"10.1097\/00125817-200103000-00010"},{"key":"2021120823002066100_R32","doi-asserted-by":"crossref","unstructured":"Dhondt JL, Farriaux JP. What do immunoreactive trypsin assays measure?Screening.\u20081994;3(1):33\u201338","DOI":"10.1016\/0925-6164(94)90033-7"},{"key":"2021120823002066100_R33","doi-asserted-by":"crossref","unstructured":"Dussault JH, Morissette J, Fiset P, Laberge E, Laberge C. Factors influencing results for thyroxine concentration in blood, as measured in paper filter spots in a screening program for neonatal hypothyroidism. Clin Chem.\u20081976;22(8):1392\u20131393","DOI":"10.1093\/clinchem\/22.8.1392"},{"key":"2021120823002066100_R34","doi-asserted-by":"crossref","unstructured":"Mitchell ML, Larsen PR, Levy HL, Bennett AJ, Madoff MA. Screening for congenital hypothyroidism. JAMA.\u20081978;239(22):2348\u20132351","DOI":"10.1001\/jama.239.22.2348"},{"key":"2021120823002066100_R35","doi-asserted-by":"crossref","unstructured":"Fisher DA, Dussault JH, Foley TP, et al. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr.\u20081979;94(5):700\u2013705","DOI":"10.1016\/S0022-3476(79)80133-X"},{"key":"2021120823002066100_R36","unstructured":"Wilson JM, Jungner G. Principles and Practice for Disease: Public Health Papers No. 34. Geneva, Switzerland: World Health Organization; 1968"},{"key":"2021120823002066100_R37","doi-asserted-by":"crossref","unstructured":"Balfour-Lynn IM. Newborn screening for cystic fibrosis: evidence for benefit. Arch Dis Child.\u20082008;93(1):7\u201310","DOI":"10.1136\/adc.2007.115832"},{"key":"2021120823002066100_R38","doi-asserted-by":"crossref","unstructured":"Rock MJ, Mischler EH, Farrell PM, Bruns WT, Hassemer DJ, Laessig RH. Immunoreactive trypsinogen screening for cystic fibrosis: characterization of infants with a false positive screening test. Pediatr Pulmonol.\u20081989;6(1):42\u201348","DOI":"10.1002\/ppul.1950060111"},{"key":"2021120823002066100_R39","doi-asserted-by":"crossref","unstructured":"Giusti R; New York State Cystic Fibrosis Newborn Screening Consortium. Elevated IRT levels in African-American infants: implications for newborn screening in an ethnically diverse population. Pediatr Pulmonol.\u20082008;43(7):638\u2013641","DOI":"10.1002\/ppul.20824"},{"key":"2021120823002066100_R40","doi-asserted-by":"crossref","unstructured":"Scotet V, De Braekeleer M, Andrezet MP, et al. Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis. Clin Genet.\u20082001;59(1):42\u201347","DOI":"10.1034\/j.1399-0004.2001.590107.x"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/123\/2\/e338\/1125298\/zpe0020900e338.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/123\/2\/e338\/1125298\/zpe0020900e338.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T13:00:58Z","timestamp":1709989258000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/123\/2\/e338\/69453\/Clarification-of-Laboratory-and-Clinical-Variables"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,1]]},"references-count":40,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2009,2,1]]},"published-print":{"date-parts":[[2009,2,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2008-1681","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2,1]]}}}