Robert Currier

Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

IMPORTANCE Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. OBJECTIVES To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN Epidemiological and retrospective observational study. SETTING Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: Results of the first 2 years

BACKGROUND Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID). OBJECTIVE We sought to report the first 2 years of TREC NBS in California. METHODS Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked. RESULTS Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry. CONCLUSIONS TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population.

Neural tube defect prevalence in California (1990-1994): eliciting patterns by type of defect and maternal race/ethnicity.

This study presents race/ethnicity-specific prevalence estimates of neural tube defects (NTDs) in California using 5 years of population-based data. NTD prevalence estimates include prenatally diagnosed cases, as well as cases diagnosed at birth. The California NTD Registry contains NTD case reports identified through the California Maternal Serum Alpha-Feto Protein (AFP) Screening Program, the California Birth Defects Monitoring Program, and additional reports from clinicians and clinics throughout the state. These data were used to estimate NTD prevalence in a large population-based study (n = 1,618,279). The overall NTD prevalence among White, Black, Hispanic, and Asian women are reported, as well as race/ethnic prevalence, for anencephaly, spina bifida, and encephalocele. Rates are expressed as the number of cases per 1,000 women screened between 1990 and 1994. Among 1,457 women with an NTD-affected pregnancy, the overall rate for anencephaly, spina bifida, and encephalocele was 0.49 (95% CI 0.46-0.53), 0.42 (95% CI 0.38-0.45), and 0.08 (95% CI 0.07-0.09), respectively. When these types of NTDs are combined, Hispanic women had the highest overall rate (1.12, 95% CI 1.04-1.21), followed by Whites (0.96, 95% CI 0.89-1.04), Blacks (0.75, 95% CI 0.59-0.91), and Asians (0.75, 95% CI 0.60-0.90). Hispanic women were 45% more likely than White women to have a pregnancy affected with anencephaly (odds ratio = 1.45, 95% CI 1.24-1.70), while Asian women were over two times less likely to have a pregnancy affected with spina bifida (odds ratio = 0.44, 95% CI 0.29-0.65). Considerable variation exists in the prevalence of NTDs by race/ethnicity and by type of NTD, with Hispanic women exhibiting the highest overall NTD rate.

Chromosome Abnormalities Detected by Current Prenatal Screening and Noninvasive Prenatal Testing

OBJECTIVE: To estimate how many additional chromosomal abnormalities can be detected by diagnostic testing compared with noninvasive prenatal testing in a high-risk prenatal population. METHODS: All karyotype results of invasive prenatal testing in singleton pregnancies performed in response to a positive prenatal screen through the California Prenatal Screening Program from April 2009 through December 2012 were examined. Abnormal karyotypes were categorized as to whether the abnormality is detectable by current noninvasive prenatal testing methods. RESULTS: Of 1,324,607 women who had traditional screening during the study period, 68,990 (5.2%) were screen-positive. Of screen-positive women, 26,059 (37.8%) underwent invasive diagnostic testing and 2,993 had an abnormal result (11.5%). Of these, 2,488 (83.1%) were predicted to be detectable with current noninvasive prenatal testing methods, and 506 (16.9%) were considered not currently detectable. Trisomy 21 accounted for 53.2% of the abnormal results (n=1,592). Common aneuploidies, detectable by noninvasive prenatal testing, comprised a higher percentage of abnormal results in older women (P<.01). CONCLUSION: For pregnant women with a positive aneuploidy screen who pursued diagnostic testing, 16.9% of chromosome abnormalities are not currently detectable by noninvasive prenatal testing. Undetectable aneuploidies range from relatively mild to those associated with significant disability. This is important information to be considered by patients, health care providers, and screening programs in evaluating the use of traditional screening and invasive prenatal diagnosis compared with noninvasive prenatal testing. LEVEL OF EVIEDENCE: III

Postanalytical tools improve performance of newborn screening by tandem mass spectrometry.

Purpose:The purpose of this study was to compare performance metrics of postanalytical interpretive tools of the Region 4 Stork collaborative project to the actual outcome based on cutoff values for amino acids and acylcarnitines selected by the California newborn screening program.Methods:This study was a retrospective review of the outcome of 176,186 subjects born in California between 1 January and 30 June 2012. Raw data were uploaded to the Region 4 Stork Web portal as .csv files to calculate tool scores for 48 conditions simultaneously using a previously unpublished functionality, the tool runner. Scores for individual target conditions were deemed informative when equal or greater to the value representing the first percentile rank of known true-positive cases (17,099 cases in total).Results:In the study period, the actual false-positive rate and positive predictive value were 0.26 and 10%, respectively. Utilization of the Region 4 Stork tools, simple interpretation rules, and second-tier tests could have achieved a false-positive rate as low as 0.02% and a positive predictive value >50% by replacing the cutoff system with Region 4 Stork tools as the primary method for postanalytical interpretation.Conclusion:Region 4 Stork interpretive tools, second-tier tests, and other evidence-based interpretation rules could have reduced false-positive cases by up to 90% in California.Genet Med 16 12, 889–895.

Birth prevalence of disorders detectable through newborn screening by race/ethnicity

Purpose:The purpose of this study was to describe the birth prevalence of genetic disorders among different racial/ethnic groups through population-based newborn screening data.Methods:Between 7 July 2005 and 6 July 2010 newborns in California were screened for selected metabolic, endocrine, hemoglobin, and cystic fibrosis disorders using a blood sample collected via heel stick. The race and ethnicity of each newborn was self-reported by the mother at the time of specimen collection.Results:Of 2,282,138 newborns screened, the overall disorder detection rate was 1 in 500 births. The disorder with the highest prevalence among all groups was primary congenital hypothyroidism (1 in 1,706 births). Birth prevalence for specific disorders varied widely among different racial/ethnic groups.Conclusion:The California newborn screening data offer a unique opportunity to explore the birth prevalence of many genetic disorders across a wide spectrum of racial/ethnicity classifications. The data demonstrate that racial/ethnic subgroups of the California newborn population have very different patterns of heritable disease expression. Determining the birth prevalence of these disorders in California is a first step to understanding the short- and long-term medical and treatment needs faced by affected communities, especially those groups that are impacted by more severe disorders.Genet Med 2012:14(11):937–945

Newborn Screening for Cystic Fibrosis in California

OBJECTIVES: This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California. METHODS: From July 16, 2007, to June 30, 2012, a total of 2 573 293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values ≥62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with ≥2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling. RESULTS: Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test–positive infants, respectively). CONCLUSIONS: The 3-step model had high detection and low false-positive levels in this diverse population.

California's Experience Implementing a Pilot Newborn Supplemental Screening Program Using Tandem Mass Spectrometry

OBJECTIVE. In response to a California legislative mandate, a pilot tandem mass spectrometry (MS/MS) screening program was undertaken by the Genetic Disease Branch of the California Department of Health Services between January 2002 and June 2003. This article outlines the Genetic Disease Branch approach to implementing the MS/MS pilot program and the program evaluation strategies used. METHODS. Through the use of multiple data collection methods, we were able to describe hospital participation patterns, screening test uptake, screening test performance, follow-up services utilization, and provider and family satisfaction with the educational materials and follow-up services provided. RESULTS. During the 18-month pilot program, just more than one half of Californias 755698 newborns were offered MS/MS screening; among this group, 90% of parents chose to have their newborns screened. Fifty-one newborns were identified with MS/MS-detectable disorders, among 461 patients referred for follow-up testing (0.13% of the screened population). One disorder was diagnosed successfully for every 6939 newborns screened and for every 9 infants referred (excluding phenylketonuria). The overall California population prevalence of MS/MS-detectable disorders was 1 case per 6500 infants (excluding phenylketonuria). The positive predictive value for medium-chain acyl-CoA dehydrogenase deficiency was 86.7%, whereas the positive predictive value for short-chain acyl-CoA dehydrogenase deficiency was 21.6%. For a sample from Hawaii, 1 isovaleric aciduria case was detected among 6132 newborns. CONCLUSIONS. Evaluation of the California MS/MS screening pilot program demonstrated that this technology was effective in identifying additional metabolic disorders. The positive predictive value of screening was particularly good for medium-chain acyl-CoA dehydrogenase deficiency. Overall, patient referral rates were very acceptable. The utility of the program was also demonstrated by positive reviews from patients and providers.

Risk of selected structural abnormalities in infants after increased nuchal translucency measurement

OBJECTIVE We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants. STUDY DESIGN Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL). RESULTS When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4). CONCLUSION Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies.

Integrated and first trimester prenatal screening in California: program implementation and patient choice for follow‐up services

The California Prenatal Screening Program serves over 350 000 women annually. This study examines utilization rates for the various screening options and patient choices regarding follow‐up services.