A Novel Approach to Improve Newborn Screening for Congenital Hypothyroidism by Integrating Covariate-Adjusted Results of Different Tests into CLIR Customized Interpretive Tools.

Newborn screening for congenital hypothyroidism remains challenging decades after broad implementation worldwide. Testing protocols are not uniform in terms of targets (TSH and/or T4) and protocols (parallel vs. sequential testing; one or two specimen collection times), and specificity (with or without collection of a second specimen) is overall poor. The purpose of this retrospective study is to investigate the potential impact of multivariate pattern recognition software (CLIR) to improve the post-analytical interpretation of screening results. Seven programs contributed reference data (N = 1,970,536) and two sets of true (TP, N = 1369 combined) and false (FP, N = 15,201) positive cases for validation and verification purposes, respectively. Data were adjusted for age at collection, birth weight, and location using polynomial regression models of the fifth degree to create three-dimensional regression surfaces. Customized Single Condition Tools and Dual Scatter Plots were created using CLIR to optimize the differential diagnosis between TP and FP cases in the validation set. Verification testing correctly identified 446/454 (98%) of the TP cases, and could have prevented 1931/5447 (35%) of the FP cases, with variable impact among locations (range 4% to 50%). CLIR tools either as made here or preferably standardized to the recommended uniform screening panel could improve performance of newborn screening for congenital hypothyroidism.

Expanded Screening of One Million Swedish Babies with R4S and CLIR for Post-Analytical Evaluation of Data.

Sweden has one neonatal screening laboratory, receiving 115 to 120 thousand samples per year. Among the one million babies screened by tandem mass spectrometry from November 2010 until July 2019, a total of 665 babies were recalled and 311 verified as having one of the diseases screened for with this methodology, giving a positive predictive value (PPV) of 47% and an incidence of 1:3200. The PPV was high (41%) already in the first year after start of screening, thanks to the availability of the collaborative project Region 4 Stork database. The PPV is presently 58%. This improvement was achieved by the implementation of second-tier analyses in the screening for methylmalonic aciduria, propionic aciduria, isovaleric aciduria, and homocystinuria, and the employment of various post analytical tools of the Region 4 Stork, and its successor the collaborative laboratory integrated reports.

GJB2 (Connexin 26) gene mutations among hearing-impaired persons in a Swedish cohort.

CONCLUSION: The most common mutation in the Swedish population was Connexin 26 (C×26) 35delG, which indicates that the percentage of Swedish persons with C×26 mutations and polymorphisms in the GJB2 gene among non-syndromic hearing-impaired (HI) persons is comparable to the rest of Europe. The results strongly support a Swedish policy to offer all children with diagnosed hearing impairment genetic tests for the C×26 35delG mutation. OBJECTIVES: The aim of the present study was to search for mutations in the GBJ2 gene among Swedish persons with non-syndromic hearing impairment to further clarify how common these mutations are in Sweden, one of the northernmost countries in Europe. METHODS: Seventy-nine patients with non-syndromic hearing impairment participated in the study. For 87% of the participants, a pure tone audiogram showed a severe or profound hearing impairment. Dried blood spots on filter paper, taken at 3-5 days of age in the Swedish nationwide neonatal screening programme for congenital disorders and saved in a biobank, were used for the molecular genetic analyses. RESULTS: The total number of subjects with one or two pathologic mutations or a mutation of unknown consequence found in the GJB2 gene was 28 of 79 (35%). Nineteen (19) persons (24%) were homozygotes for the 35delG mutation.

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.

PURPOSE: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25­30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders.