{'fraction_non_alphanumeric': 0.026595744680851064, 'fraction_numerical': 0.026595744680851064, 'mean_word_length': 4.825854700854701, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Newborn screening for severe combined immunodeficiency: progress and challenges.

September 30, 2014, marks the 50th anniversary of the Children’s Bureau recommendation for “the screening of all newborn infants for PKU [phenylketonuria] on a routine basis.”1 By 1968, 43 states had made screening for PKU mandatory.1 As a result of technological advances, newborn screening in the United States has been extended to as many as 37 core conditions in some states.2 As reported by Kwan and colleagues3 in this issue of JAMA, newborn screening for severe combined immunodeficiency (SCID) has been undertaken in 23 states and the Navajo Nation, beginning in Wisconsin in January 2008. The authors present data on more than 3 million newborns screened with a T-cell receptor excision circle (TREC) assay followed by confirmatory flow cytometry from 11 of these programs (10 states and the Navajo Nation). Have these programs absorbed lessons from the first 50 years of newborn screening? In 1975, a committee of the National Academy of Sciences considered the lessons of the first 10 years. The committee noted: “Screening was started, frequently under mandatory laws, when questions regarding diagnosis, prognosis, and optimal management were unanswered.”1 Each of these questions with regard to SCID screening deserves examination. Diagnosis. Because tests that diagnose a disorder with perfect validity are often expensive and sometimes lengthy to perform, screening tests suitable for entire populations almost always yield false-positive test results requiring costly recall of healthy infants, perturbing them and their parents unnecessarily. This wide net is cast to ensure that infants who have the disorder and whose initial screening test result can vary are not missed by screening (false negatives). In the study by Kwan et al,3 of the 11 programs providing data on SCID screening, the cutoff in the TREC assay was set at less than 40 TREC/μL in 8 programs and less than 252 TREC/μL in 3 programs. Excluding the Navajo Nation, in which a founder effect mutation in the DCLRE1C gene increased the incidence of SCID to 1 in 3500, the data reported by Kwan et al yield a ratio of total TREC-positive results to SCID infants detected by confirmatory tests to be 91.1 (291.7 referrals for flow cytometry per 100 000 screened/3.2 mean SCID diagnosed per 100 000 screened) in the 7 programs with the most stringent cutoffs (<40 TREC/μL) compared with 170.5 (255.8 referrals/ 1.5 diagnosed) in the 3 programs with the more inclusive cutoffs (<252 TREC/μL). In the study, no infants with SCID were missed by screening. However, the authors did not report the actual TREC results of the infants diagnosed with SCID, so the extent to which lowering the cutoffs will reduce the number of false-positive infants without missing infants with SCID cannot be ascertained. The data are currently under analysis in the R4S project, which incorporates factors in addition to the TREC result to identify “presumptive positive” infants for referral for definitive diagnosis.4 This method should reduce the number of false positives for SCID without increasing the number of false negatives (Piero Rinaldo, Mayo Clinic College of Medicine, written communication, July 4, 2014). The TREC assay, based on real-time polymerase chain reaction to detect the small piece of DNA that is excised from lymphocytes when they become T cells, resulted in the detection of 52 infants with SCID involving 11 different genes. In 8 of the 52, no known SCID mutation was found. Thus, the phenotypic TREC assay has proven more efficient than single-gene assays and is much less costly than whole-genome sequencing, which might miss mutations previously unknown to cause SCID. The observed SCID incidence of 1 in 58 000 births reported by Kwan et al3 is greater than the previously assumed incidence based on clinical detection and exceeds the criterion of a US panel that a condition should have an incidence of greater than 1 in 100 000 to qualify for inclusion in newborn screening.5 Prognosis. The ability to improve outcomes is a cardinal criterion for screening and there is no doubt that newborn SCID screening has saved lives and improved their quality. In the report by Kwan et al,3 of the 52 SCID infants diagnosed, 49 received immunity restoring therapies, of whom 45 survived (92%). The early deaths of 3 infants who were not treated were attributable to other conditions. Without early detection by screening, some of the survivors most likely would have died, some of them without a diagnosis. Of the 411 infants with nonSCID T-cell lymphopenia, only 4 were treated. This small proportion justifies the authors’ conclusion that the “usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.” Optimal Management. For disorders like SCID that may be fatal in the first months of life, early screening and prompt diagnosis are essential. The authors observed that 175 infants with “a nonnormal TREC... died before further testing could be done.” They acknowledge the possibility that “some of these infants had SCID, [although] SCID is not known to lead to death in the newborn period” (in the first footnote to Table 23). It would be important to know the ages at which these deceased newborns were screened and whether follow-up was delayed. However, data were not available to Kwan et al on the Related article page 729 Opinion