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PEDIATRICS Vol. 113 No. 6 June 2004, pp. 1573-1581

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

Anne Marie Comeau, PhD^*, Richard B. Parad, MD, MPH^*,, Henry L. Dorkin, MD, Mark Dovey, MD, Robert Gerstle, MD^||, Kenan Haver, MD^¶, Allen Lapey, MD^¶, Brian P. O'Sullivan, MD^#, David A. Waltz, MD, Robert G. Zwerdling, MD^# and Roger B. Eaton, PhD^*

^* New England Newborn Screening Program of University of Massachusetts Medical School, Boston, Massachusetts
The Children's Hospital, Boston, Massachusetts
New England Medical Center, Boston, Massachusetts
^|| Baystate Medical Center Children's Hospital, Springfield, Massachusetts
^¶ Massachusetts General Hospital, Boston, Massachusetts
^# University of Massachusetts Memorial Health Care, Worcester, Massachusetts

Objectives. Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (F508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders. The objective of this study was to evaluate technical feasibility and practical implications of 2-tiered CF newborn screening that uses testing for multiple mutations (multiple-CFTR-mutation testing).

Methods. We implemented statewide CF newborn screening using a 2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT then had multiple-CFTR-mutation testing. Infants who screened positive by detection of 1 or 2 mutations or extremely elevated IRT (>99.8%; failsafe protocol) were then referred for definitive diagnosis by sweat testing. We compared the number of sweat-test referrals using single- with multiple-CFTR-mutation testing. Initial physician assessments and diagnostic outcomes of these screened-positive infants and any affected infants missed by the screen were analyzed. We evaluated compliance with our screening and follow-up protocols. All Massachusetts delivery units, the Newborn Screening Program, pediatric health care providers who evaluate and refer screened-positive infants, and the 5 Massachusetts CF Centers and their affiliated genetic services participated. A 4-year cohort of 323 506 infants who were born in Massachusetts between February 1, 1999, and February 1, 2003, and screened for CF at 2 days of age was studied.

Results. A total of 110 of 112 CF-affected infants screened (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation screening; 2 false-negative screens did not show elevated IRT. A total of 107 (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation screen, and 3 had positive screens on the basis of the failsafe protocol. In contrast, had we used single-mutation testing, only 96 (87%) of the 110 would have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had positive screens on the basis of the failsafe protocol, and an additional 6 infants would have had false-negative screens. Among 110 CF-affected screened-positive infants, a likely "genetic diagnosis" was made by the multiple-CFTR-mutation screen in 82 (75%) versus 55 (50%) with F508 alone. Increased sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals for sweat testing and carrier identifications than testing with F508 alone.

Conclusions. Use of multiple-CFTR-mutation testing improved sensitivity and postscreening prediction of CF at the cost of increased referrals and carrier identification.

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Key Words: newborn screening • genetic screening • population screening • cystic fibrosis screening • cystic fibrosis • multiple-mutation testing • DNA screening

Abbreviations: CF, cystic fibrosis • MA-CF, Massachusetts CF newborn screening program • IRT, immunoreactive trypsinogen • CFTR, cystic fibrosis transmembrane conductance regulator • CFF, Cystic Fibrosis Foundation • NENSP, New England Newborn Screening Program • [IRT], IRT concentration • Cl^–, chloride • QNS, quantity not sufficient • NPV, negative predictive value PPV, positive predictive value • CI, confidence interval

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Received for publication Aug 25, 2003; Accepted Oct 23, 2003.

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