Molecular Genetics and Metabolism 86 (2005) 427–430 www.elsevier.com/locate/ymgme 1096-7192/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2005.09.005 Two-tiered universal newborn screening strategy for severe combined immunodeWciency Sean A. McGhee a,¤ , E. Richard Stiehm a , Morton Cowan b , Paul Krogstad c , Edward R.B. McCabe d a Department of Pediatrics/Immunology, David GeVen School of Medicine, University of California, Los Angeles, USA b Department of Pediatric Bone Marrow Transplantation, University of California, San Francisco, USA c Department of Pediatrics/Infectious Disease, David GeVen School of Medicine, University of California, Los Angeles, USA d Department of Pediatrics and Department of Human Genetics, David GeVen School of Medicine, University of California, Los Angeles, USA Received 16 September 2005; accepted 16 September 2005 Available online 2 November 2005 Abstract Outcomes for infants with severe combined immunodeWciency (SCID) would be improved by universal newborn screening, but there are not yet screening tests of suYcient accuracy for the disorder. In a pilot study, we assessed the ability of a two-tiered strategy to improve accuracy. Dried blood samples from patients were assessed with two tests for lymphopenia: interleukin-7, a T-cell growth cyto- kine, and TRECs, a byproduct of T-cell receptor recombination. IL-7 screening has a speciWcity of 96.1% and TRECs have a speciWcity of 92.3%. Combining these tests in a two-tiered strategy increases speciWcity to 100% (97–100% CI). Sensitivity was 85% for IL-7 screening and 100% for TREC screening. A two-tiered strategy may be of suYcient accuracy to enable universal SCID screening, and should be assessed in a prospective trial.  2005 Elsevier Inc. All rights reserved. Keywords: Interleukin-7; TRECs; Newborn screening; ImmunodeWciency; Severe combined immunodeWciency; Lymphopenia Introduction Newborn screening for genetic disease has been an enor- mously successful public health eVort, and the number of disorders on screening panels has been increasing [1]. In general, disorders that beneWt from screening are diYcult to detect without systematic screening, have clearly beneWcial treatments available, and have inexpensive and accurate screening tests. Severe combined immunodeWciency (SCID) meets many of these characteristics, but is not currently on newborn screening panels. SCID is a lethal disorder of adaptive immunity without overt signs or symptoms prior to the development of life-threatening infections [2]. Treatment is by stem cell transplantation, which can be done for almost all patients. Furthermore, early therapy improves outcomes and screening would enable greater detection of cases [3]. Screening for SCID has been proposed by a National Insti- tutes of Health study committee [4], but implementation has been hindered by the lack of inexpensive and speciWc tests that can be performed from the dried blood samples that are used by newborn screening programs [5]. Some promising tests are in development, such as the measurement by PCR of T-cell receptor recombination excision circles (TRECs), small circular DNA fragments generated in the development of T cells [6]. However, even this test is not adequately speciWc. The presumed rarity of SCID (1:70,000–100,000 live births) [4] means that even in highly speciWc tests, there is a low positive predictive value. We have estimated that a SCID screening test would require a speciWcity of at least 97% to be cost eVective, assuming society is willing to pay $100,000 for every * Corresponding author. Fax: +1 310 825 9832. E-mail address: smcghee@mednet.ucla.edu (S.A. McGhee).