, 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.

Purpose: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. Methods: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. Results: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. Conclusions: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%

Blood carnitine and/or acetylcarnitine deficiencies are postulated in the literature as possible causes of higher ammonia levels. The aim of this study was to investigate if the use of valproic acid, the age of the patients, or certain central nervous system pathologies can cause carnitine and/or acetylcarnitine deficiency leading to increased ammonia levels. Three groups of patients were studied: (A) epileptic under phenytoin monotherapy (n = 31); (B) with bipolar disorder under valproic acid treatment (n = 28); (C) elderly (n = 41). Plasma valproic acid and blood carnitine and acyl carnitine profiles were determined using a validated HPLC and LC-MS/MS method, respectively. Blood ammonia concentration was determined using an enzymatic automated assay. Higher ammonia levels were encountered in patients under valproic acid treatment and in the elderly. This may be due to the lower carnitine and/or acetylcarnitine found in these patients. Patients with controlled seizures had normal carnitine and acetylcarnitine levels. Further studies are necessary in order to conclude if the uncontrolled bipolar disorder could be the cause of higher carnitine and/or acetylcarnitine levels.

Introduction: Newborn Screening Program (NBS) in Uruguay includes congenital hypothyroidism (CHT), phenylketonuria (PKU), congenital adrenal hyperplasia (CAH), cystic fibrosis (CF), medium chain acyl-CoA dehydrogenase deficiency (MCADD), and Congenital Hearing Loss (CHL). Objetives: This study describe the epidemiological characteristics of newborns with abnormal neonatal screening tests diagnosed by blood drop and otoacoustic emissions in Uruguay. Results: Cases with abnormal NBS tests (399 newborns; 0.17%) were compared to the newborns with normal tests in the same period (239,240). Prevalence rates (per 10,000 livebirths) were 10.00 for CHL; 3.70 for CH; 1.20 for CF; 0.59 for CAH; 0.54 for PKU; 0.13 for MCADD. The Department of Artigas had the highest rate of abnormal tests. Lower maternal education, less prenatal care, increased prematurity rate and neonatal depression were more frequent in in mothers whose children had CHL. Conclusions: This is the first study evaluating the characteristics of newborns with abnormal screening in Uruguay. Because these results may impact the planning of health services, data transmission between clinical care and public health systems is needed to improve both follow-up and management.

In the 1960s Guthrie conceived the idea of preventing congenital disease using dried blood spot samples on filter paper to detect them through biochemical tests and then be able to treat environmental factors in time to avoid the devastating effect of the diseases. Uruguay started in 1994 with the detection of congenital hypothyroidism in umbilical cord blood. In 2007 it was extended to Phenylketonuria and Congenital Adrenal Hyperplasia, starting with dried blood spot sample. In 2008, with the incorporation of Mass Spectrometry, a pilot program was started for the detection of aminoacidopathies, beta-oxidation defects and organic acidemias disorders. In the following years, the program expanded to more diseases, reaching a total of 25 disorders that could be detected, 5 of them are investigated on a mandatory basis and others in pilot program. During the 25-year of experience, 974277 umbilical cord blood samples were analyzed and since 2007: 532684 dried blood spot samples. 613 true positive congenital disorders were identified. The coverage has been greater than 98% and the repetition rate for insufficient samples less than 1.9%.