Quality of nuchal translucency measurements correlates with broader aspects of program rigor and culture of excellence.

INTRODUCTION: To determine if nuchal translucency (NT) quality correlates with the extent to which clinics vary in rigor and quality control. METHODS: We correlated NT performance quality (bias and precision) of 246,000 patients with two alternative measures of clinic culture - % of cases for whom nasal bone (NB) measurements were performed and % of requisitions correctly filled for race-ethnicity and weight. RESULTS: When requisition errors occurred in <5% of cases, the average MoM (multiple of the median) was 0.97. When >5% (33%), the curve lowered to 0.93 MoM (p < 0.001) with both bias and precision of measurements impaired. Likewise, for centers with NB >90%, MoM was 0.99 compared to those <10% at 0.93 (p < 0.001). Precision and bias were highly correlated (p < 0.001). CONCLUSIONS: Rigor in NT measurements has improved, but the discussion has been confined to individuals. Progressive educational and remediation strategies need to expand to a second dimension - clinics themselves. Cross-clinic variation in NT quality exists independent of individual variation in NT quality, and two divergent indices of program rigor are associated with NT quality. Quality control must be program wide, and to effect continued improvement in the quality of NT results across time, the cultures of clinics must become a target for intervention.

First-trimester screening in triplets.

OBJECTIVE: The purpose of this study was to determine the performance of Down syndrome screening in triplet pregnancy. STUDY DESIGN: Nuchal translucency (NT; n = 794), nasal bone (n = 219), and biochemistry (n = 198) were evaluated in triplet pregnancy. Screening performance was evaluated with the use of delta and Gaussian models. RESULTS: The median multiples of the median values for free beta human chorionic gonadotropin and pregnancy-associated plasma protein A were 2.86 and 3.48, respectively. A significant correlation in delta NT within pregnancy was observed (0.46-0.68). The modeled false-positive rates were 11.7%, 7.4%, and 8.9% with the delta model and 11.9%, 6.6%, and 12.0% with the Gaussian model for NT, NT + nasal bone, and NT + biochemistry. Based on simulation, the detection rate at 12 weeks' gestation was 78%, 93%, and 80% for NT, NT + nasal bone, and NT + biochemistry at a 10% false-positive rate using either the delta or Gaussian models. CONCLUSION: In triplet pregnancy, the addition of nasal bone lowers the false-positive rate of nuchal translucency screening. More data are required on the effectiveness of biochemistry.

First trimester Down syndrome screening with dried blood spots using a dual analyte free beta hCG and PAPP-A immunofluorometric assay.

OBJECTIVE: To determine the effectiveness of first trimester Down syndrome screening with dried blood spots using a dual analyte free beta human chorionic gonadotrophin (hCG)/pregnancy-associated plasma protein A (PAPP-A) immunofluorometric assay. METHOD: An initial retrospective study of 54 Down syndrome cases and 1064 control specimens was performed followed by a series of 146,513 specimens from routine screening. Detection rates at a fixed 5% false-positive rate were determined separately based on reference data from the retrospective study set and then adjusted based on the routine screening study set. RESULTS: On the basis of the retrospective analysis, the estimated detection rate using free beta hCG, PAPP-A and maternal age varied from 78% at 9 weeks of pregnancy to 70% at 13 weeks of pregnancy. Using a combined protocol, including NT, the detection rate varied from 92 to 90% between 9 and 13 weeks of gestation. Adjusting distribution parameters based on the routine screening dataset reduced the detection rate by at most 1%. CONCLUSION: Analysis of free beta hCG and PAPP-A using a dual analyte dried blood spot assay is an effective tool in Down syndrome screening, adding an important option for those considering implementation or modification of existing prenatal screening programs.

Identification of novel and rare mutations in California Hispanic and African American cystic fibrosis patients.

In ethnic heterogeneous California, complete genetic information is currently lacking to build solid population-based cystic fibrosis (CF) screening programs because a large proportion of mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR/ABCC7) are still unknown, especially in non-Caucasian patients. A total of 402 [46 African American+356 Hispanic] Hispanic and African American patients from California CF patient registry were included in this study. Patients with at least one unidentified mutant allele were asked to donate blood samples for further analysis, first by Genzyme Genetics for a panel of 87 known mutations, followed by temporal temperature gradient gel electrophoresis (TTGE) scanning of the entire coding exons of CFTR gene. A total of eight novel mutations; one missense mutation, one splice-site mutation and six frame-shift mutations were identified. In addition to the eight novel mutations, 20 [corrected] distinct rare mutations that are not in the current available commercial mutation panels were identified by TTGE. The overall detection rate was raised to 95.7% for African American and 94.5% for Hispanic. The discovery of recurrent rare and novel mutations improves the diagnosis and care of persons with CF and improves our ability to adequately and equitably provide screening and genetic counseling services to non-Caucasians.

Screening for open neural tube defects.

Maternal serum screening for congenital anomalies began over 30 years ago with the advent of alpha-fetoprotein (AFP) screening for open neural tube defects. It was from these screening programs that the more complex multiple marker Down syndrome screening programs developed. However, today open neural tube defect screening remains a relatively simple approach. In recent times, questions arise about the validity of the risk assessment associated with neural tube defect screening because of the impact of folate acid enrichment in diets and lack of outcome ascertainment. However, it still remains true that those with elevated AFP levels are at higher risk for having a pregnancy affected with open neural tube defect.

Undermeasurement of nuchal translucencies: implications for screening.

OBJECTIVE: To analyze the maximum nuchal translucency from 327 centers to determine whether a more-than-expected number of centers had maximum nuchal translucency of 2.5 mm or less (approximately 4% of nuchal translucency values should be 2.5 mm or higher). METHODS: We analyzed data from 182,669 nuchal translucency cases at centers in which at least 100 nuchal translucency examinations were performed from July 2008 through June 2009 and investigated the appropriateness of the distribution of values. We then investigated the likelihood of the skewing of the distribution seen using a 100 simulations of such modeled data. RESULTS: Based on a binomial distribution, the chance that a center would have no nuchal translucency values above 2.5 mm is 1.7% for 100 patients per center, and 0.2% for 150 patients per center. Additionally, the median multiples of the median should shift by approximately 2.5% if all nuchal translucency values higher than 2.5 mm are excluded from the population. Our data show that 7.3% of centers had a maximum nuchal translucency of to 2.5 mm or less, and more than 20% have never reported an nuchal translucency of greater than 3 mm. The maximum nuchal translucency at a center correlated positively with its median multiple of the median. Centers with no nuchal translucency values greater than 2.5 mm also have nearly 50% of their ultrasonographers with excessive low nuchal translucency (greater than 10% of cases less than fifth percentile). CONCLUSION: Too many centers have a maximum nuchal translucency of 2.5 mm or lower, low median nuchal translucency, and excessive low nuchal translucency, indicating that data from these centers are not representative of the expected distribution of nuchal translucencies. Our data suggest a systematic undermeasurement of nuchal translucency. LEVEL OF EVIDENCE: III.

Pilot programs in newborn screening.

The term "pilot study" has been used over the years to describe the evaluation of the many elements involved in deciding whether a proposed condition should be added to a newborn screening (NBS) panel, and until recently, was unilaterally used to describe the evaluation of the assay to be used before the condition was officially adopted by a state for its newborn screening panel. Since Guthrie's introduction of screening for PKU, each time a new condition was added to the panel, the screening assay itself was validated through a population-based trial, in which the test was performed with de-identified samples to avoid association between the test result and the infant. This is considered by the laboratory as the "pilot phase" of adding a new condition. To advance the science of NBS, especially to accommodate new technologies that may provide new types of information (genetic versus physiological) for each new condition, pilot programs are essential. Involvement of the clinical community serves to improve these evaluations and provides the needed clinical validation of decisions made as a result of it. This paper describes the historical context of pilot programs in population-based NBS that utilize laboratory-based markers as indicators of concern; specifically, three applications that demonstrate different approaches to the use of pilots in adding conditions to a NBS panel are described.

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 California's 755,698 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.

Retrospective determination of ceruloplasmin in newborn screening blood spots of patients with Wilson disease.

Wilson disease is an autosomal recessive disorder of copper transport, caused by the reduced or absent function of the Wilson disease gene ATP7B on chromosome 13. The disease is characterized by reduced incorporation of copper into the ceruloplasmin protein and reduced excretion of copper into the bile. Wilson disease is effectively treated if detected early. Our study goals were to determine the feasibility of a population screening for Wilson disease using dried blood spots and to characterize the base-line ceruloplasmin concentration in newborn blood spots of patients with Wilson disease. Ceruloplasmin was analyzed in dried blood spots obtained from 353 Mayo Clinic pediatric volunteers aged from 3 months to 18 years and from 1045 anonymous newborn screening specimens using a sandwich enzyme-linked immunosorbent assay. The original newborn screening blood spots were retrieved from two patients with Wilson disease along with age-matched controls for ceruloplasmin determination. The mean (+/-SD) concentration of ceruloplasmin in the pediatric blood spots was 40.0+/-14.4 mg/dL (range 13.1 to >60 mg/dL) and newborn blood spots was 47.2+/-15.5mg/dL (range 6.5 to >60 mg/dL). Ceruloplasmin in the newborn blood spots from two Wilson disease patients were 2.6 and 2.8 mg/dL, respectively. The newborns affected with Wilson disease had significantly lower ceruloplasmin levels in blood spots than unaffected newborns. These findings support that presymptomatic screening for Wilson disease using dried blood spots could be possible, even in the newborn period.