1. Newborn Screening via Tandem Mass Spectrometry, Michigan, 2006 Steven Korzeniewski, MS, MA, William Young, PhD, and Violanda Grigorescu, MD, MSPH, Michigan Department of Community Health, Division of Genomics, Perinatal Health and Chronic Disease Epidemiology ABSTRACT: Background: Since tandem mass spectrometry (TMS) was introduced in 2003, the Michigan Newborn Screening Program (MI NBS) has expanded to include 41 TMS detectable disorders as recommended by the American College of Medical Genetics (ACMG). This study reports screening performance metrics for year 2006, when screening for all ACMG recommended TMS disorders became Michigan law. Study Question: What are the performance metrics for TMS screening in Michigan, 2006? Methods: Vital Statistics data collected by the Michigan Department of Community Health (MDCH) were used to calculate the total number of live births eligible to be screened in Michigan. To identify positive cases and case-related information we utilized Perkin Elmer systems and data collected at the Medical Management Centers in databases developed/maintained by the NBS follow-up program. Thus, we were able to both determine the total number of cases and describe the population screened. Cases were: a) identified through the newborn screening, b) diagnosed through established protocols, and c) Michigan residents. Performance metrics reported include detection rates, false positive rates, and positive predictive values. Results: MI NBS screened 99.6% of the 126,509 live births occurring in Michigan in 2006. Overall, 10.8% of infants screened were in neonatal intensive care units, 1.4% were born with a weight less than 1500g, and 0.6% were born prior to 28 weeks gestational age. Of the 261 positive screens, 35 infants were diagnosed as having a TMS disorder. The TMS disorder detection rate was 1: 3,589, the positive predictive value was 13.4%, and the false positive rate was 0.18%. Conclusions: TMS screening has revolutionized newborn screening. The performance metrics measured in this study indicate that the use of TMS is a significant and cost-effective improvement over the use of other single disorder screening methodologies. Public Health Implications: The use of cost effective screening (TMS) will allow for better allocation of resources and further improvement of follow-up. Moreover, the improvement of performance metrics would lead to better standards of diagnostics and care. Little is known about TMS disorders and so we must also take the opportunity to develop disease specific registries as part of long term follow-up efforts. ABSTRACT: Background: Since tandem mass spectrometry (TMS) was introduced in 2003, the Michigan Newborn Screening Program (MI NBS) has expanded to include 41 TMS detectable disorders as recommended by the American College of Medical Genetics (ACMG). This study reports screening performance metrics for year 2006, when screening for all ACMG recommended TMS disorders became Michigan law. Study Question: What are the performance metrics for TMS screening in Michigan, 2006? Methods: Vital Statistics data collected by the Michigan Department of Community Health (MDCH) were used to calculate the total number of live births eligible to be screened in Michigan. To identify positive cases and case-related information we utilized Perkin Elmer systems and data collected at the Medical Management Centers in databases developed/maintained by the NBS follow-up program. Thus, we were able to both determine the total number of cases and describe the population screened. Cases were: a) identified through the newborn screening, b) diagnosed through established protocols, and c) Michigan residents. Performance metrics reported include detection rates, false positive rates, and positive predictive values. Results: MI NBS screened 99.6% of the 126,509 live births occurring in Michigan in 2006. Overall, 10.8% of infants screened were in neonatal intensive care units, 1.4% were born with a weight less than 1500g, and 0.6% were born prior to 28 weeks gestational age. Of the 261 positive screens, 35 infants were diagnosed as having a TMS disorder. The TMS disorder detection rate was 1: 3,589, the positive predictive value was 13.4%, and the false positive rate was 0.18%. Conclusions: TMS screening has revolutionized newborn screening. The performance metrics measured in this study indicate that the use of TMS is a significant and cost-effective improvement over the use of other single disorder screening methodologies. Public Health Implications: The use of cost effective screening (TMS) will allow for better allocation of resources and further improvement of follow-up. Moreover, the improvement of performance metrics would lead to better standards of diagnostics and care. Little is known about TMS disorders and so we must also take the opportunity to develop disease specific registries as part of long term follow-up efforts. Table 1: Amino Acid Disorders, Screening Performance Metrics, Michigan, 2006 Amino Acid Disorder Total + N (% NICU) Confirmed + (N) Detection Rate FPR (%) PPV (%) Phenylketonuria -Classic (PKU) 20 (5.0) 31: 41,8660.0115.0 Mild61: 20,9330.0130.0 Benign Hypephenyla-laninemia (H-PHE)61: 20,9330.0130.0 Biopterin Cofactor Defects (BIOPT)--0.02- Total 151: 8,3730.00475.0 Maple Syrup Urine Disease (MSUD)4 (25.0)000.0030 Homocystinuria (HCY)5 (0.0)000.0040 Arginemia (ARG)3 (100)000.0020 Citrullinemia/ASA** (CIT/ASA)7 (14.3)11 : 125,6000.00514.3 Tyrosinemia (TYR I)13 (61.5)000.010 Fatty Acid Oxidation Disorders Total + N (% NICU) Confirmed + (N) Detection Rate FPR (%) PPV (%) Carnitine/Acylcarnitine Translocase Deficiency- (CACT) 3 (0.0)0-0.0020 Carnitine Uptake Defect- (CUP) 19 (31.6)0-0.020 Carnitine Palmitoyltransferase I Deficiency- (CPT 1A) 6 (33.3)0-0.010 Carnitine Palmitoyltransferase II Deficiency-(CPT II) 3 (33.3 )0-0.0020 Short-Chain Acyl-CoA Dehydrogenase deficiency- (SCAD) 15 (40.0)0-0.010 Glutaric Acidemia Type II- (GA II) 1 (100.0)0-0.0010 Medium-Chain Acyl-CoA Dehydrogenase Deficiency- (MCAD) 10 (10.0 )91 : 13,9550.00190.0 Long-Chain L-30H Acyl-CoA Dehydrogenase Deficiency- (LCHAD) 1 (100.0)11 : 125,6000100 Very Long-Chain Acyl-CoA Dehydrogenase Deficiency- (VLCAD) 4 (0.0)11 : 125,6000.00225.0 Medium-Chain Ketoacyl-CoA Thiolase Deficiency- (MCKAT) 3 (0.0)0-0.0020 Tryfunctional Protein Disease- (TFP) 10 (0.0)0-0.0080 Table 2 Organic Acid Disorders, Screening Performance Metrics, Michigan, 2006 Organic Acid DisordersTotal+ N(% NICU) Confirmed+ (N) Detection Rate FPR (%) PPV (%) Isovaleric Acidemia (IVA)17 (58.8)11 : 125,6000.015.9 3-Methylcrotonyl-CoA Carboxylase Deficiency37 (16.2)11 : 125,6000.0292.7 Glutaric Acidemia Type I (GA I)7 (28.6)21 : 62,8930.00428.6 Proprionic Acidemia/MMA (PA)58 (34.4)0-0.0460 Methylmalonic Acidemia (Mutase Deficiency) MA58 (34.4)21 : 62,8930.0453.4 Methylmalonic Acidemia (MA-Cbl C, D)58 (34.4)11 : 125,6000.0451.7 Isobutyryl-CoA Dehydrogenase Deficiency (IBG)15 (0.0)11 : 125,6000.017.1 2-Methylbutyryl-CoA Dehydrogenase Deficiency (2MBG) 17 (58.8)0-0.010 Table 3: Fatty Acid Oxidation Disorders, Screening Performance Metrics, Michigan, 2006 Figure 1: Overview of the Michigan Newborn Screening Program INTRODUCTION: The introduction of tandem mass spectrometry (TMS) in 2003 enabled the Michigan newborn screening (NBS) laboratory to efficiently screen for a large number of disorders detectable from a single blood spot. In 2005, a pilot project was initiated to expand the screening panel to 48 disorders by adding the additional TMS disorders recommended by the American College of Medical Genetics (ACMG) and the March of Dimes. This study reports TMS screening performance metrics for year 2006, when screening for all ACMG recommended TMS disorders became Michigan law. METHODS: Vital Statistics data collected by the Michigan Department of Community Health (MDCH) were used to calculate the total number of live births eligible to be screened in Michigan. To identify positive cases and case- related information we utilized Perkin Elmer systems and data collected at the Medical Management Centers in databases developed/maintained by the NBS follow-up program. Thus, we were able to both determine the total number of cases and describe the population screened. Cases were: a) identified through the newborn screening, b) diagnosed through established protocols, and c) Michigan residents. Performance metrics reported include detection rates, false positive rates (FPR), and positive predictive values (PPV). Performance metric targets for TMS disorders are based on the work of Piero Rinaldo, M.D., Ph.D., et al. (2006) recently reported in Mental Retardation and Developmental Disability Reviews. (Rinaldo, P., Zafari, S., Tortorelli, S., and Matern, D. (2006) Making The Case for Objective Performance Metrics In Newborn Screening by Tandem Mass Spectrometry. Mental Retardation and Developmental Disabilities Research Reviews. 12: 255-261.) RESULTS: Of the 261 positive TMS screens, 35 cases were confirmed. While the overall FPR for Michigan TMS screening (0.18%) is below the target of 0.3%, the PPV (13.4%) and detection rate (1:3,589) approach but do not meet the target metrics suggested by Rinaldo, et al. in 2006 (PPV > 20%, Detection rate 1:3,000). Tables 1, 2, and 3 report screening performance metrics for amino acid, organic acid, and fatty acid oxidation disorders respectively. FPRs for each disorder were less than the performance metric target of 0.3%. Only screening for PKU (in total and other than for classic form), GA type I, MCAD, LCHAD, and VLCAD PPVs exceeded the performance metric target of 20%. CONCLUSIONS: TMS screening is a significant, cost-effective improvement over other methodologies that screen for single disorders. Little is known about most inborn errors of metabolism detected by TMS. Now that these disorders can be diagnosed via NBS prior to symptom onset we have new opportunities to refine treatment and disease management strategies to improve patient outcomes. To do so, new paradigms of treatment and management are necessary. We also have an opportunity to learn more about genotype/phenotype correlations by studying how gene environment interactions influence the expression of these diseases. However, to seize these opportunities we must first learn from each other by engaging in discourse about screening methods, outcomes, and follow-up strategies, including both successes and failures via dissemination of our findings to advance the field of NBS as a whole as requested by Pierro et al. (2006). We must also take the opportunity to develop disease specific registries as part of long term NBS follow-up efforts. Registries would provide access to the study population necessary for the conduct of current and future research aimed towards advancing our understanding of inborn errors of metabolism. TMS is allowing us to embark on new opportunities to advance public health, we have a unique opportunity to make a collaborative effort to broaden our understanding of inborn errors of metabolism at a rate far quicker than any of us could do alone. Public Health Implications: The use of cost effective TMS screening will allow for better allocation of resources and further improvement of NBS follow-up. Moreover, the improvement of performance metrics will lead to better standards of diagnostics and care.