, Melissa Yssel, MB ChB, FC Path(SA) Chem 139, and Wendy M. Zakowicz, BS 79 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 25-30 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.

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.

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.

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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.

The prevalence of the 985A>G mutation in the medium-chain acyl-CoA dehydrogenase gene was determined in the Swedish population. A heterozygote frequency of 1:127 was observed. Morbidity data indicate that most of the homozygotes with this mutation are not diagnosed and probably remain asymptomatic.

Natural abundance carbon 13 magnetic resonance spectroscopy (I3C MRS) allows the proportion of saturated and unsaturated fatty acids in adipose tissue to be measured repeatedly and non-invasively. Eleven infants and two of their mothers underwent "C MRS. Ten infants were studied in the first week of life, one also at 6 weeks and one at 10 weeks only. Using an enveloping transmitter coil and a surface receiver coil, coupled 13C spectra were obtained with repetition times of 0.3 seconds and 30 seconds. These were analysed by the NMRl curve fitting program and the percentages of saturated and unsaturated fatty acids calculated'. The results are shown either individually or as the median and range in the 60, 8340, 17 One of the two mothers studied, a vegan, had a higher proportion of unsaturated fatty acids compared to the other mother who consumed a mixed diet (87% vs 71%). These preliminary results suggest that "C MRS might be used to perform longitudinal studies of different influences on the composition of adipose tissue in infants. There i s no consistent c l i n i c a l presentation i n the patients detected by metabolic investigation and thymine-uraciluria has been observed i n healthy subjects -i s the finding pathogenic?Jane M. Hawdon, Melisa Jarvis, Penny Clark, C. Nick Hales Neonatal Unit, Liverpool Maternity Hospital, University of Liverpool, and Department of Clinical Biochemistry. University of Cambridge.Recent studies have shown that neonatal insulin-glucose relationships differ to those of older children. The aim of this study was to determine whether crossreatiwity with proinsulin-like molecules accounted for this finding.Daily venous blood samples were collected from 18 neonates (median gest. 30 weeks) in the first postnatal week. Blood glucose concentration (BG) was determined by microenzymatic methods and plasma concentrations of insulin, proinsulin (proins) and des 31.32 split proinsulin (31-32 spl) were measured by specific IRMA.Mean (sem) BG was 4.5 (0.2) mmol/l. Median (range) concentrations for insulin, proins and 31 -32 spl were 35 (5-1 99). 12 (5-30), and 19 (9-44) pmolll. On mukiple regression analysis BG correlated negatively with gestation (p<0.001) and positively with glucose infusion rate (p<0.01); there was a positive correlation between plasma insulin concentration and BG (p<0.001) which was independent of gestational and postnatal age and birthweight standard deviatio;, score; an3 independent negative correlations for proins with gestational and postnatal age (p<0.01, p<0.01).These data suggest that plasma insulin concentrations may be overestimated unless a specific assay is used. There is a controversy whether, in addition to phenylalanine (PHE), produc of PHE transamination are involved in the pathogenesis of phenylketonur (PKU). We determined phenyllactate in plasma by HPLC and PHE by ami acid analysis monthly for half a year in 24 adult patients with classic PK who had stopped diet. Phenyllactate was measurable in all plasma samp (mean: 52 pmol/l; range: 7-154; mean PHE. 1250...