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Therrell BL, Padilla CD, Borrajo GJC, Khneisser I, Schielen PCJI, Knight-Madden J, Malherbe HL, Kase M. Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020-2023). Int J Neonatal Screen 2024; 10:38. [PMID: 38920845 PMCID: PMC11203842 DOI: 10.3390/ijns10020038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 06/27/2024] Open
Abstract
Newborn bloodspot screening (NBS) began in the early 1960s based on the work of Dr. Robert "Bob" Guthrie in Buffalo, NY, USA. His development of a screening test for phenylketonuria on blood absorbed onto a special filter paper and transported to a remote testing laboratory began it all. Expansion of NBS to large numbers of asymptomatic congenital conditions flourishes in many settings while it has not yet been realized in others. The need for NBS as an efficient and effective public health prevention strategy that contributes to lowered morbidity and mortality wherever it is sustained is well known in the medical field but not necessarily by political policy makers. Acknowledging the value of national NBS reports published in 2007, the authors collaborated to create a worldwide NBS update in 2015. In a continuing attempt to review the progress of NBS globally, and to move towards a more harmonized and equitable screening system, we have updated our 2015 report with information available at the beginning of 2024. Reports on sub-Saharan Africa and the Caribbean, missing in 2015, have been included. Tables popular in the previous report have been updated with an eye towards harmonized comparisons. To emphasize areas needing attention globally, we have used regional tables containing similar listings of conditions screened, numbers of screening laboratories, and time at which specimen collection is recommended. Discussions are limited to bloodspot screening.
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Affiliation(s)
- Bradford L. Therrell
- Department of Pediatrics, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA
- National Newborn Screening and Global Resource Center, Austin, TX 78759, USA
| | - Carmencita D. Padilla
- Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines;
| | - Gustavo J. C. Borrajo
- Detección de Errores Congénitos—Fundación Bioquímica Argentina, La Plata 1908, Argentina;
| | - Issam Khneisser
- Jacques LOISELET Genetic and Genomic Medical Center, Faculty of Medicine, Saint Joseph University, Beirut 1104 2020, Lebanon;
| | - Peter C. J. I. Schielen
- Office of the International Society for Neonatal Screening, Reigerskamp 273, 3607 HP Maarssen, The Netherlands;
| | - Jennifer Knight-Madden
- Caribbean Institute for Health Research—Sickle Cell Unit, The University of the West Indies, Mona, Kingston 7, Jamaica;
| | - Helen L. Malherbe
- Centre for Human Metabolomics, North-West University, Potchefstroom 2531, South Africa;
- Rare Diseases South Africa NPC, The Station Office, Bryanston, Sandton 2021, South Africa
| | - Marika Kase
- Strategic Initiatives Reproductive Health, Revvity, PL10, 10101 Turku, Finland;
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Karaca Sahin M, Aktuglu Zeybek AC, Zubarioglu T, Cansever MS, Kıykım E. Comparison of Cost Analysis in Patients with Tetrahydrobiopterin-Responsive and Non-Responsive Phenylketonuria in Turkey. Nutrients 2024; 16:1444. [PMID: 38794682 PMCID: PMC11124297 DOI: 10.3390/nu16101444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 05/26/2024] Open
Abstract
Phenylketonuria is an inherited metabolic disorder that leads to neurobehavioral dysfunction. The main treatment is a low-phenylalanine diet and/or the cofactor tetrahydrobiopterin. Regular outpatient follow-up care and measurement of the phenylalanine levels in the blood are required. We aimed to analyze the economic burden of phenylketonuria on families and the state. The patients with phenylketonuria were divided into three groups according to their treatment: a low-phenylalanine diet group (n = 50), a tetrahydrobiopterin group (n = 44), and a group taking tetrahydrobiopterin together with the diet (n = 25). A comparative cost analysis was carried out. The annual economic burden to the state was calculated to average EUR 18,801 ± 15,345 and was lowest in the diet group, then in the tetrahydrobiopterin group, and highest in the tetrahydrobiopterin + diet group (p < 0.001). Out-of-pocket costs amounted to EUR 1531 ± 1173 per year, and indirect losses averaged EUR 2125 ± 1930 per year for all families. The economic loss was significantly lower in the families taking tetrahydrobiopterin than in the other groups (p = 0.001). The combined use of medical nutrition and BH4 treatments has been shown to increase the economic burden on the state. Reimbursing low-protein products and increasing the number of patients eligible for financial allowances may reduce the economic burden on families.
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Affiliation(s)
- Merve Karaca Sahin
- Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey;
| | - Ayse Cigdem Aktuglu Zeybek
- Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey; (A.C.A.Z.); (T.Z.)
| | - Tanyel Zubarioglu
- Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey; (A.C.A.Z.); (T.Z.)
| | - Mehmet Serif Cansever
- Division of Medical Laboratory Techniques, Department of Medical Documentation and Techniques, The Vocational School of Health Services, Istanbul University-Cerrahpasa, 34295 Istanbul, Turkey;
| | - Ertugrul Kıykım
- Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey; (A.C.A.Z.); (T.Z.)
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Panchbudhe SA, Shivkar RR, Banerjee A, Deshmukh P, Maji BK, Kadam CY. Improving newborn screening in India: Disease gaps and quality control. Clin Chim Acta 2024; 557:117881. [PMID: 38521163 DOI: 10.1016/j.cca.2024.117881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/18/2024] [Accepted: 03/19/2024] [Indexed: 03/25/2024]
Abstract
In India, newborn screening (NBS) is essential for detecting health problems in infants. Despite significant progress, significant gaps and challenges persist. India has made great strides in genomics dueto the existence of the National Institute of Biomedical Genomics in West Bengal. The work emphasizes the challenges NBS programs confront with technology, budgetary constraints, insufficient counseling, inequality in illness panels, and a lack of awareness. Advancements in technology, such as genetic testing and next-generation sequencing, are expected to significantly transform the process. The integration of analytical tools, artificial intelligence, and machine learning algorithms could improve the efficiency of newborn screening programs, offering a personalized healthcare approach. It is critical to address gaps in information, inequities in illness incidence, budgetary restrictions, and inadequate counseling. Strengthening national NBS programs requires increased public awareness and coordinated efforts between state and central agencies. Quality control procedures must be used at every level for implementation to be successful. Additional studies endeavor to enhance NBS in India through public education, illness screening expansion, enhanced quality control, government incentive implementation, partnership promotion, and expert training. Improved neonatal health outcomes and the viability of the program across the country will depend heavily on new technology and counseling techniques.
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Affiliation(s)
- Sanjyoti A Panchbudhe
- Shrimati Kashibai Navale Medical College and General Hospital, Narhe, Pune 411041, Maharashtra, India
| | - Rajni R Shivkar
- Shrimati Kashibai Navale Medical College and General Hospital, Narhe, Pune 411041, Maharashtra, India
| | - Arnab Banerjee
- Department of Physiology (UG & PG), Serampore College, 9 William Carey Road, Serampore, Hooghly 712201, West Bengal, India
| | - Paulami Deshmukh
- Shrimati Kashibai Navale Medical College and General Hospital, Narhe, Pune 411041, Maharashtra, India
| | - Bithin Kumar Maji
- Department of Physiology (UG & PG), Serampore College, 9 William Carey Road, Serampore, Hooghly 712201, West Bengal, India
| | - Charushila Y Kadam
- Department of Biochemistry, Sukh Sagar Medical College and Hospital, Jabalpur 482003, Madhya Pradesh, India.
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Zou YG, Wang H, Li WW, Dai DL. Challenges in pediatric inherited/metabolic liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders. World J Gastroenterol 2023; 29:2114-2126. [PMID: 37122598 PMCID: PMC10130973 DOI: 10.3748/wjg.v29.i14.2114] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/09/2023] [Accepted: 03/21/2023] [Indexed: 04/13/2023] Open
Abstract
The clinical scenario of pediatric liver disease is becoming more intricate due to changes in the disease spectrum, in which an increasing number of inherited/ metabolic liver diseases are reported, while infectious diseases show a decreasing trend. The similar clinical manifestations caused by inherited/metabolic diseases might be under-recognized or misdiagnosed due to nonspecific characteristics. A delayed visit to a doctor due to a lack of symptoms or mild symptoms at an early stage will result in late diagnosis and treatment. Moreover, limited diagnostic approaches, especially liver biopsy, are not easily accepted by pediatric patients, leading to challenges in etiological diagnosis. Liver dysfunction due to inherited/metabolic diseases is often caused by a variety of metabolites, so precision treatment is difficult; symptomatic treatment is a compelling option for inherited disorders.
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Affiliation(s)
- Yi-Gui Zou
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Huan Wang
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Wen-Wen Li
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Dong-Ling Dai
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
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Lefèvre CR, Labarthe F, Dufour D, Moreau C, Faoucher M, Rollier P, Arnoux JB, Tardieu M, Damaj L, Bendavid C, Dessein AF, Acquaviva-Bourdain C, Cheillan D. Newborn Screening of Primary Carnitine Deficiency: An Overview of Worldwide Practices and Pitfalls to Define an Algorithm before Expansion of Newborn Screening in France. Int J Neonatal Screen 2023; 9:6. [PMID: 36810318 PMCID: PMC9944086 DOI: 10.3390/ijns9010006] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/24/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
Primary Carnitine Deficiency (PCD) is a fatty acid oxidation disorder that will be included in the expansion of the French newborn screening (NBS) program at the beginning of 2023. This disease is of high complexity to screen, due to its pathophysiology and wide clinical spectrum. To date, few countries screen newborns for PCD and struggle with high false positive rates. Some have even removed PCD from their screening programs. To understand the risks and pitfalls of implementing PCD to the newborn screening program, we reviewed and analyzed the literature to identify hurdles and benefits from the experiences of countries already screening this inborn error of metabolism. In this study, we therefore, present the main pitfalls encountered and a worldwide overview of current practices in PCD newborn screening. In addition, we address the optimized screening algorithm that has been determined in France for the implementation of this new condition.
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Affiliation(s)
| | - François Labarthe
- Reference Center of Inherited Metabolic Disorders, Clocheville Hospital, 37000 Tours, France
| | - Diane Dufour
- Reference Center of Inherited Metabolic Disorders, Clocheville Hospital, 37000 Tours, France
| | | | | | - Paul Rollier
- Rennes University Hospital Center, 35033 Rennes, France
| | - Jean-Baptiste Arnoux
- Reference Center for Inborn Error of Metabolism, Department of Pediatrics, Necker-Enfants Malades Hospital, APHP, 75015 Paris, France
| | - Marine Tardieu
- Reference Center of Inherited Metabolic Disorders, Clocheville Hospital, 37000 Tours, France
| | - Léna Damaj
- Rennes University Hospital Center, 35033 Rennes, France
| | | | - Anne-Frédérique Dessein
- Metabolism and Rare Disease Unit, Department of Biochemistry and Molecular Biology, Center of Biology and Pathology, Lille University Hospital Center, 59000 Lille, France
| | - Cécile Acquaviva-Bourdain
- Center for Inherited Metabolic Disorders and Neonatal Screening, East Biology and Pathology Department, Groupement Hospitalier Est (GHE), Hospices Civils de Lyon, 69500 Bron, France
| | - David Cheillan
- Center for Inherited Metabolic Disorders and Neonatal Screening, East Biology and Pathology Department, Groupement Hospitalier Est (GHE), Hospices Civils de Lyon, 69500 Bron, France
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Martín‐Rivada Á, Palomino Pérez L, Ruiz‐Sala P, Navarrete R, Cambra Conejero A, Quijada Fraile P, Moráis López A, Belanger‐Quintana A, Martín‐Hernández E, Bellusci M, Cañedo Villaroya E, Chumillas Calzada S, García Silva MT, Bergua Martínez A, Stanescu S, Martínez‐Pardo Casanova M, Ruano MLF, Ugarte M, Pérez B, Pedrón‐Giner C. Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region. JIMD Rep 2022; 63:146-161. [PMID: 35281663 PMCID: PMC8898721 DOI: 10.1002/jmd2.12265] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/21/2022] Open
Abstract
We present the results of our experience in the diagnosis of inborn errors of metabolism (IEM) since the Expanded Newborn Screening was implemented in our Region. Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by mass spectrometry (MS)/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed. In the period 2011 to 2019, 592 822 children were screened: 902 of them were referred for abnormal results. An IEM was confirmed in 222 (1/2670): aminoacidopathies: 89 hyperphenylalaninemia (HPA) (51 benign HPA, 32 phenylketonuria, 4 DNAJC12 defect, and 2 primapterinuria), 6 hypermethioninemia, 3 tyrosinemia type 1 (TYR-1), 1 TYR-3, 4 maple syrup urine disease (MSUD), 2 branched-chain amino acid transferase 2 deficiency, 2 homocystinuria, 1 cystinuria, 2 ornithine transcarbamylase (OTC) deficiency, 2 citrullinemia type I (CTLN1); FAO defects: 43 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 13 very long-chain acyl-CoA dehydrogenase deficiency, 2 long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), 1 multiple acyl-coA dehydrogenation deficiency, 11 systemic primary carnitine deficiency, 2 carnitine palmitoyltransferase type 2 (CPT-II) deficiency, 1 CPT-I deficiency; organic acidurias: 12 glutaric aciduria type 1 (GA-1), 4 methylmalonic acidemia (MMA), 7 MMA including combined cases with homocystinuria (MMAHC), 6 propionic acidemia (PA), 7 3-methylcrotonyl-CoA carboxylase, 1 3-hydroxy-3-methylglutaryl-CoA lyase deficiency lyase deficiency. Only 19 infants (8.5%) were symptomatic at newborn screening result (1 LCHADD, 5 PA, 1 CPT-II deficiency, 1 MMA, 3 MMAHC, 2 MSUD, 2 OTC deficiency, 1 CTLN1, 1 MCADD, 2 TYR-1). No false negative cases were identified. Genetic diagnosis was conclusive in all biochemically confirmed cases, except for two infants with HPA, identifying pathogenic variants in 32 different genes. The conditions with the highest incidence were HPA (1/6661) and MCAD deficiencies (1/13 787).
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Affiliation(s)
- Álvaro Martín‐Rivada
- Sección de Gastroenterología y NutriciónHospital Infantil Universitario Niño JesúsMadridSpain
| | - Laura Palomino Pérez
- Sección de Gastroenterología y NutriciónHospital Infantil Universitario Niño JesúsMadridSpain
| | - Pedro Ruiz‐Sala
- Centro de Diagnóstico de Enfermedades MolecularesUniversidad Autónoma de Madrid, IdiPAZ, CIBERERMadridSpain
| | - Rosa Navarrete
- Centro de Diagnóstico de Enfermedades MolecularesUniversidad Autónoma de Madrid, IdiPAZ, CIBERERMadridSpain
| | - Ana Cambra Conejero
- Laboratorio de Cribado Neonatal de la Comunidad de MadridServicio de Bioquímica Clínica, Hospital General Universitario Gregorio MarañónMadridSpain
| | - Pilar Quijada Fraile
- Unidad de Enfermedades Mitocondriales‐Metabólicas HereditariasCentro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de OctubreMadridSpain
| | - Ana Moráis López
- Unidad de Nutrición Infantil y Enfermedades MetabólicasHospital Universitario La PazMadridSpain
| | - Amaya Belanger‐Quintana
- Centro de Referencia Nacional (CSUR) en Enfermedades MetabólicasHospital Universitario Ramón y CajalMadridSpain
| | - Elena Martín‐Hernández
- Unidad de Enfermedades Mitocondriales‐Metabólicas HereditariasCentro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de OctubreMadridSpain
| | - Marcello Bellusci
- Unidad de Enfermedades Mitocondriales‐Metabólicas HereditariasCentro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de OctubreMadridSpain
| | - Elvira Cañedo Villaroya
- Sección de Gastroenterología y NutriciónHospital Infantil Universitario Niño JesúsMadridSpain
| | - Silvia Chumillas Calzada
- Unidad de Enfermedades Mitocondriales‐Metabólicas HereditariasCentro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de OctubreMadridSpain
| | - María Teresa García Silva
- Unidad de Enfermedades Mitocondriales‐Metabólicas HereditariasCentro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metabólicas, Hospital Universitario 12 de OctubreMadridSpain
| | - Ana Bergua Martínez
- Unidad de Nutrición Infantil y Enfermedades MetabólicasHospital Universitario La PazMadridSpain
| | - Sinziana Stanescu
- Centro de Referencia Nacional (CSUR) en Enfermedades MetabólicasHospital Universitario Ramón y CajalMadridSpain
| | | | - Miguel L. F. Ruano
- Laboratorio de Cribado Neonatal de la Comunidad de MadridServicio de Bioquímica Clínica, Hospital General Universitario Gregorio MarañónMadridSpain
| | - Magdalena Ugarte
- Centro de Diagnóstico de Enfermedades MolecularesUniversidad Autónoma de Madrid, IdiPAZ, CIBERERMadridSpain
| | - Belén Pérez
- Centro de Diagnóstico de Enfermedades MolecularesUniversidad Autónoma de Madrid, IdiPAZ, CIBERERMadridSpain
| | - Consuelo Pedrón‐Giner
- Sección de Gastroenterología y NutriciónHospital Infantil Universitario Niño JesúsMadridSpain
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Padilla CD, Therrell BL, Alcausin MMLB, Chiong MAD, Abacan MAR, Reyes MEL, Jomento CM, Dizon-Escoreal MTT, Canlas MAE, Abadingo ME, Posecion JEWC, Abarquez CG, Andal AP, Elizaga ALG, Halili-Mendoza BC, Otayza MPVK, Millington DS. Successful Implementation of Expanded Newborn Screening in the Philippines Using Tandem Mass Spectrometry. Int J Neonatal Screen 2022; 8:ijns8010008. [PMID: 35225931 PMCID: PMC8883932 DOI: 10.3390/ijns8010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 12/23/2021] [Accepted: 01/12/2022] [Indexed: 11/29/2022] Open
Abstract
Newborn bloodspot screening (NBS) began as a research project in the Philippines in 1996 and was mandated by law in 2004. The program initially included screening for five conditions, with a sixth added in 2012. As screening technology and medical knowledge have advanced, NBS programs in countries with developed economies have also expanded, not only in the number of newborns screened but also in the number of conditions included in the screening. Various approaches have been taken regarding selection of conditions to be screened. With limited resources, low- and middle-income countries face significant challenges in selecting conditions for screening and in implementing sustainable screening programs. Building on expansion experiences in the U.S. and data from California on Filipinos born and screened there, the Philippine NBS program has recently completed its expansion to include 29 screening conditions. This report focuses on those conditions detectable through tandem mass spectrometry. Expanded screening was implemented in a stepwise fashion across the seven newborn screening laboratories in the Philippines. A university-based biochemical genetics laboratory provides confirmatory testing. Follow-up care for confirmed cases is monitored and provided through the NBS continuity clinics across the archipelago. Pre-COVID-19 pandemic, the coverage was 91.6% but dropped to 80.4% by the end of 2020 due to closure of borders between cities, provinces, and islands.
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Affiliation(s)
- Carmencita D. Padilla
- Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines; (M.M.L.B.A.); (M.E.L.R.); (C.M.J.); (M.T.T.D.-E.); (M.A.E.C.); (M.E.A.)
- Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (M.A.D.C.); (M.A.R.A.)
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines
- Correspondence:
| | - Bradford L. Therrell
- National Newborn Screening and Global Resource Center, Austin, TX 78759, USA;
- Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Maria Melanie Liberty B. Alcausin
- Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines; (M.M.L.B.A.); (M.E.L.R.); (C.M.J.); (M.T.T.D.-E.); (M.A.E.C.); (M.E.A.)
- Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (M.A.D.C.); (M.A.R.A.)
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines
| | - Mary Anne D. Chiong
- Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (M.A.D.C.); (M.A.R.A.)
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines
- Department of Biochemistry, Molecular Biology and Nutrition, Faculty of Medicine and Surgery, University of Santo Tomas, Manila 1008, Philippines
| | - Mary Ann R. Abacan
- Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (M.A.D.C.); (M.A.R.A.)
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines
| | - Ma. Elouisa L. Reyes
- Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines; (M.M.L.B.A.); (M.E.L.R.); (C.M.J.); (M.T.T.D.-E.); (M.A.E.C.); (M.E.A.)
| | - Charity M. Jomento
- Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines; (M.M.L.B.A.); (M.E.L.R.); (C.M.J.); (M.T.T.D.-E.); (M.A.E.C.); (M.E.A.)
| | - Maria Truda T. Dizon-Escoreal
- Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines; (M.M.L.B.A.); (M.E.L.R.); (C.M.J.); (M.T.T.D.-E.); (M.A.E.C.); (M.E.A.)
| | - Margarita Aziza E. Canlas
- Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines; (M.M.L.B.A.); (M.E.L.R.); (C.M.J.); (M.T.T.D.-E.); (M.A.E.C.); (M.E.A.)
| | - Michelle E. Abadingo
- Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines; (M.M.L.B.A.); (M.E.L.R.); (C.M.J.); (M.T.T.D.-E.); (M.A.E.C.); (M.E.A.)
| | | | - Conchita G. Abarquez
- Newborn Screening Center—Mindanao, Southern Philippine Medical Center, Davao 8000, Philippines;
| | - Alma P. Andal
- Newborn Screening Center—Southern Luzon, Daniel O. Mercado Medical Center, Tanauan 4232, Philippines;
| | - Anna Lea G. Elizaga
- Newborn Screening Center—National Institutes of Health, Quezon 1101, Philippines;
| | - Bernadette C. Halili-Mendoza
- Newborn Screening Center—Central Luzon, Angeles University Foundation Medical Center, Angeles 2009, Philippines;
| | - Maria Paz Virginia K. Otayza
- Newborn Screening Center—Northern Luzon, Mariano Marcos Memorial Hospital and Medical Center, Batac 2906, Philippines;
| | - David S. Millington
- Department of Pediatrics, Duke University School of Medicine, Durham, NC 27708, USA;
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Chandran J, Bellad A, Ramarajan MG, Rangiah K. Applications of quantitative metabolomics to revolutionize early diagnosis of inborn errors of metabolism in India. ANALYTICAL SCIENCE ADVANCES 2021; 2:546-563. [PMID: 38715861 PMCID: PMC10989570 DOI: 10.1002/ansa.202100010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/05/2021] [Accepted: 05/08/2021] [Indexed: 11/17/2024]
Abstract
Inborn errors of metabolism (IEMs) are a group of disorders caused by disruption of metabolic pathways, which leads to accumulation, decreased circulating levels, or increased excretion of metabolites as a consequence of the underlying genetic defects. These heterogeneous groups of disorders cause significant neonatal and infant mortality across the whole world and it is of utmost concern for developing countries like India owing to lack of awareness and standard preventive strategies like newborn screening (NBS). Though the predictive cumulative incidence of IEMs is said to be ∼1:800 newborns, data pertaining to the true prevalence of individual IEMs is not available in the context of Indian population. There is a need for a large population-based study to get a clear picture of the prevalence of different IEMs. One of the best ways to screen for IEMs is by applying advanced liquid chromatography-mass spectrometry (LC-MS) technology using a quantitative metabolomics approaches such as selected or multiple reaction monitoring (SRM or MRM). Recent developments in LC-MS/MRM based quantification of marker metabolites in newborns have opened a novel opportunity to screen multiple disorders simultaneously from a minuscule volume of biological fluids. In this review article, we have highlighted how LC-MS/MRM based metabolomics approach with its high sensitivity and diagnostic capability can make an impact on the nation's public health through NBS programs.
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Affiliation(s)
| | - Anikha Bellad
- Institute of BioinformaticsBangaloreKarnatakaIndia
- Manipal Academy of Higher EducationManipalKarnatakaIndia
| | - Madan Gopal Ramarajan
- Institute of BioinformaticsBangaloreKarnatakaIndia
- Manipal Academy of Higher EducationManipalKarnatakaIndia
| | - Kannan Rangiah
- Institute of BioinformaticsBangaloreKarnatakaIndia
- Manipal Academy of Higher EducationManipalKarnatakaIndia
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NeoSeq: a new method of genomic sequencing for newborn screening. Orphanet J Rare Dis 2021; 16:481. [PMID: 34794485 PMCID: PMC8600711 DOI: 10.1186/s13023-021-02116-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/06/2021] [Indexed: 12/16/2022] Open
Abstract
Objective To explore the clinical application of NeoSeq in newborn screening. Methods Based on the results obtained from traditional newborn screening (NBS) with tandem mass spectrometry (TMS), three cohorts were recruited into the present study: 36 true positive cases (TPC), 60 false-positive cases (FPC), and 100 negative cases. The dried blood spots of the infants were analyzed with NeoSeq, which is based on multiplex PCR amplicon sequencing. Results Overall, the sensitivity of NeoSeq was 55.6% (20/36) in the detection of TPC. NeoSeq detected disease-related genes in 20 of 36 TPC infants, while it could not identify these genes in eight children. Five cases (3.1%) with disease risk were additionally found in the FPC and NC cohorts. There was a significant difference in the diagnostic time between the two methods—10 days for NeoSeq vs. 43 days for traditional NBS. Conclusions NeoSeq is an economic genomic screening test for newborn screening. It can detect most inborn errors of metabolism, reduce the rate of false positive results, shorten the porting cycles, and reduce the screening cost. However, it is still necessary to further optimize the panel design and add more clinically relevant genomic variants to increase its sensitivity. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02116-5.
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Yang N, Gong LF, Zhao JQ, Yang HH, Ma ZJ, Liu W, Wan ZH, Kong YY. Inborn errors of metabolism detectable by tandem mass spectrometry in Beijing. J Pediatr Endocrinol Metab 2020; 33:639-645. [PMID: 32304307 DOI: 10.1515/jpem-2019-0420] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 02/06/2020] [Indexed: 12/18/2022]
Abstract
Background Individual inborn errors of metabolism (IEMs) are rare disorders. Expanded newborn screening for IEMs by tandem mass spectrometry (TMS) is an efficient approach for early diagnosis. Here we provide the newborn screening program for the application of this approach (between July 2014 and March 2019) to the identification of newborns in Beijing at risk of developing a potentially fatal disease. Methods The amino acids and acylcarnitines in dried blood spots were analyzed by TMS. Diagnoses of newborns with elevated metabolites were confirmed by gas chromatography-mass spectrometry, biochemical studies, and genetic analysis. Results Among the healthy newborns, 16 metabolic disorder cases were confirmed, giving a total birth prevalence of 1:3666 live births. Organic acidemia (OA) was the most common (9/16 patients; 56%), and methylmalonic acidemia was the most frequently observed OA (7/9 patients; 89%). Five infants were diagnosed with methylmalonic acidemia with homocystinuria type CblC, two with isolated methylmalonic acidemia, one with propionic acidemia, and one with isovaleric acidemia. Four patients (4/16, 25%) were diagnosed with hyperphenylalaninemia. One suffered with medium-chain acyl CoA dehydrogenase deficiency, one with carnitine uptake deficiency, and one with citrin deficiency. Eleven cases underwent genetic analysis. Seventeen mutations in eight IEM-associated genes were identified in 11 confirmed cases. Symptoms were already present within 2 days after birth in 44% (7/16) cases. The infant with propionic acidemia died at 7 days after birth. The other cases received timely diagnosis and treatment, and most of them grew well. Conclusions The results illustrate challenges encountered in disease management highlighting the importance of newborn screening for inherited metabolic disorders, which is not yet nationally available in our country. Regional newborn screening programs will provide a better estimation of the incidence of IEM.
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Affiliation(s)
- Nan Yang
- Newborn Screening Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, P.R. China
| | - Li-Fei Gong
- Newborn Screening Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, P.R. China
| | - Jin-Qi Zhao
- Newborn Screening Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, P.R. China
| | - Hai-He Yang
- Newborn Screening Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, P.R. China
| | - Zhi-Jun Ma
- Newborn Screening Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, China
| | - Wei Liu
- Newborn Screening Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, China
| | - Zhi-Hui Wan
- Newborn Screening Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, China
| | - Yuan-Yuan Kong
- Newborn Screening Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang District, Beijing, P.R. China
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Altimimi HA, Aljawadi HF, Ali EA. Inborn Errors of Metabolism in Children with Unexplained Developmental Delay in Misan, Iraq. Oman Med J 2019; 34:297-301. [PMID: 31360317 PMCID: PMC6642708 DOI: 10.5001/omj.2019.59] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Objectives We sought to determine the prevalence of inborn errors of metabolism (IEM) in children with unexplained developmental delay and their types. Methods We conducted a cross-sectional study in Misan, Iraq, over a period of one year. A total of 112 infants with unexplained developmental delay were included in the study, and the required information was taken from their parents by direct interview. Tandem mass spectrometry (MS/MS) was done in collaboration with MedLabs’ Referral Laboratory in Amman, Jordan. Results Twenty (17.9%) cases had abnormal MS/MS. Disorders of amino acid metabolism represented the majority of IEM (10 cases) in which phenylketonuria and maple syrup urine disease were the most common (found in five cases each). Organic and fatty acid metabolisms were found in five and two cases, respectively. Most cases of IEM had a positive family history and consanguinity, however, family history was the only significant factor (p < 0.001). Conclusions A high rate of IEM was detected in children with unexplained developmental delay in Misan. A high clinical suspicion with positive family history and consanguinity supported by the MS/MS results played an essential role in the diagnosis. However, implementation of newborn screening is essential for early diagnosis and to determine appropriate therapy in newborns with IEM in Iraq generally and in Misan in particular.
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Affiliation(s)
- Hassan A Altimimi
- Pediatrics Department, Misan Hospital for Child and Maternity, Misan, Iraq
| | - Hussein F Aljawadi
- Pediatrics Department, College of Medicine, Misan University, Misan, Iraq
| | - Esraa A Ali
- Pediatrics Department, College of Medicine, Misan University, Misan, Iraq
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Moreira-Silva H, Maio I, Bandeira A, Gomes-Martins E, Santos-Silva E. Metabolic liver diseases presenting with neonatal cholestasis: at the crossroad between old and new paradigms. Eur J Pediatr 2019; 178:515-523. [PMID: 30693370 DOI: 10.1007/s00431-019-03328-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 01/15/2019] [Accepted: 01/17/2019] [Indexed: 12/18/2022]
Abstract
Metabolic liver diseases (MLD) are an important group of disorders presenting with neonatal cholestasis (NC). The spectrum of liver involvement is wide and the presumptive diagnosis is traditionally based on clinical and laboratory findings. Recently, next-generation sequencing (NGS) panels have emerged as an appealing tool to diagnose neonatal/infantile cholestatic disorders. The aim of this study was to identify clinical phenotypes of liver injury and contribute to find a diagnostic methodology that integrates new molecular diagnostic tools. We retrospectively analyzed the clinical and biochemical features of 16 patients with MLD and NC. Patients were categorized into three groups: A-NC with liver failure (N = 8): tyrosinemia type I (n = 2), classic galactosemia (n = 5), mitochondrial DNA depletion syndrome (n = 1); B-NC evolving with chronic liver disease (N = 5): argininemia (n = 2); mitochondrial cytopathy (n = 1); congenital disorders of glycosylation type Ia (n = 1); Zellweger syndrome (n = 1); and C-transient NC (N = 3): Niemann-Pick type C (n = 2), citrullinemia type II (n = 1).Conclusion: MLD presenting with NC can be categorized into three main clinical phenotypes of liver injury. We highlight transient NC as a clue for MLD that must be pursued. New molecular diagnostic tools can play a key role, but application criteria must be established to make them cost-effective. What is Known: • Metabolic liver diseases are an important group of disorders presenting with neonatal cholestasis. • The diagnostic approach is challenging and traditionally based on clinical and laboratory findings. Next-generation sequencing is a recent and rapidly developing tool in pediatric hepatology. What is New: • We provide a liver-targeted characterization of metabolic liver diseases presenting with neonatal cholestasis, categorizing them into three clinical phenotypes that may narrow the diagnostic possibilities. • A clinical decision-making algorithm is proposed, in which the NGS technology is integrated.
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Affiliation(s)
- Helena Moreira-Silva
- Pediatric Gastroenterology Unit, Centro Materno Infantil do Norte - CMIN, Centro Hospitalar Universitário do Porto, Largo da Maternidade de Júlio Dinis, 4050-651, Porto, Portugal
| | - Inês Maio
- Pediatric Gastroenterology Unit, Centro Materno Infantil do Norte - CMIN, Centro Hospitalar Universitário do Porto, Largo da Maternidade de Júlio Dinis, 4050-651, Porto, Portugal
| | - Anabela Bandeira
- Pediatric Metabolic Unit, Centro Materno Infantil do Norte - CMIN, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Esmeralda Gomes-Martins
- Pediatric Metabolic Unit, Centro Materno Infantil do Norte - CMIN, Centro Hospitalar Universitário do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal
| | - Ermelinda Santos-Silva
- Pediatric Gastroenterology Unit, Centro Materno Infantil do Norte - CMIN, Centro Hospitalar Universitário do Porto, Largo da Maternidade de Júlio Dinis, 4050-651, Porto, Portugal. .,Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal.
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Yang Y, Wang L, Wang B, Liu S, Yu B, Wang T. Application of Next-Generation Sequencing Following Tandem Mass Spectrometry to Expand Newborn Screening for Inborn Errors of Metabolism: A Multicenter Study. Front Genet 2019; 10:86. [PMID: 30838026 PMCID: PMC6382741 DOI: 10.3389/fgene.2019.00086] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 01/29/2019] [Indexed: 12/30/2022] Open
Abstract
This study explored the effectiveness of expanding newborn screening (NBS) by tandem mass spectrometry (TMS) and gene diagnosis by next-generation sequencing (NGS). First, we described the characteristics of gene variants in Jiangsu Province. We collected clinical data from three NBS centers. All infants followed a unified screening and diagnosis process. After obtaining informed consent, dried blood spots (DBSs) were collected and analyzed by TMS. If the results fell outside of the cut-off value, repeat analysis was performed. If the re-test results remained abnormal, the infant was recalled for further assessment. We performed targeted sequencing using the extended edition panel of inborn errors of metabolism (IEM) to detect 306 genes using the Illumina HiSeq 2500 platform. A total of 536,008 babies underwent NBS by TMS in three NBS centres. In total, 194 cases were eventually diagnosed with various types of inherited metabolic diseases, with an overall incidence of 1/2763. There were 23 types of diseases, including ten amino acid disorders (43.5%), eight organic acidaemias (34.8%) and five fatty acid oxidation defects (21.7%). In these infants, we clearly identified variants of disease-causing genes by next-generation sequencing (NGS). Most had two variants and others had one or three variants: 88% of gene variants were heterozygous and 12% were homozygous. There is a certain incidence of IEM in Jiangsu Province and it is necessary to carry out screening for 27 diseases. Meanwhile, NGS combined with TMS offers an enhanced plan for NBS for IEM.
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Affiliation(s)
- Yuqi Yang
- Changzhou Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Leilei Wang
- Lianyungang Maternal and Child Health Hospital Affiliated to Yangzhou University, Lianyungang, China
| | - Benjing Wang
- The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Shuang Liu
- Lianyungang Maternal and Child Health Hospital Affiliated to Yangzhou University, Lianyungang, China
| | - Bin Yu
- Changzhou Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Ting Wang
- The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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Abstract
PURPOSE OF REVIEW We review newborn screening (NBS) publications from the developing countries to identify global progress in improving child health. RECENT FINDINGS Many developing countries do not yet have national NBS. As infant mortality rates decline, NBS gains in public health priority. Local incidence and outcome data are used to persuade health officials to include screening in priority health spending. Congenital hypothyroidism is the most cost-effective screened condition in most countries. In sub-Saharan Africa, India and some parts of Asia, screening for hemoglobinopathies and glucose-6-dehydrogenase deficiency are also important. Expanded screening for metabolic conditions is most needed in areas of high consanguinity. Screening for hearing disorders and critical congenital heart defects is increasing globally. The largest birth cohorts are India and China, but only China has successful NBS. Reports from completed government research projects in India support initiation of NBS. SUMMARY Government activities around NBS are increasing in India and there is increased emphasis on pilot programs for sickle cell NBS in sub-Saharan Africa. Genetic counseling training in Asia and Africa is increasing and will be helpful as part of NBS. To build successful screening programs, partnerships among health professionals, parents, policy makers and industry stakeholders are essential.
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Abstract
Started in 1963 by Robert Guthrie, newborn screening (NBS) is considered to be one of the great public health achievements. Its original goal was to screen newborns for conditions that could benefit from presymptomatic treatment, thereby reducing associated morbidity and mortality. With advances in technology, the number of disorders included in NBS programs increased. Pompe disease is a good candidate for NBS. Because decisions regarding which diseases should be included in NBS panels are made regionally and locally, programs and efforts for NBS for Pompe disease have been inconsistent both in the United States and globally. In this article, published in the "Newborn Screening, Diagnosis, and Treatment for Pompe Disease" guidance supplement, the Pompe Disease Newborn Screening Working Group, an international group of experts in both NBS and Pompe disease, review the methods used for NBS for Pompe disease and summarize results of current and ongoing NBS programs in the United States and other countries. Challenges and potential drawbacks associated with NBS also are discussed.
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Affiliation(s)
- Olaf A Bodamer
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts;
| | - C Ronald Scott
- Division of Molecular Medicine, Department of Pediatrics, University of Washington, Seattle, Washington; and
| | - Roberto Giugliani
- Medical Genetics Service, Hospital de Clinicas de Porto Alegre (HCPA) and Department of Genetics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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Wagner M, Tonoli D, Varesio E, Hopfgartner G. The use of mass spectrometry to analyze dried blood spots. MASS SPECTROMETRY REVIEWS 2016; 35:361-438. [PMID: 25252132 DOI: 10.1002/mas.21441] [Citation(s) in RCA: 162] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Dried blood spots (DBS) typically consist in the deposition of small volumes of capillary blood onto dedicated paper cards. Comparatively to whole blood or plasma samples, their benefits rely in the fact that sample collection is easier and that logistic aspects related to sample storage and shipment can be relatively limited, respectively, without the need of a refrigerator or dry ice. Originally, this approach has been developed in the sixties to support the analysis of phenylalanine for the detection of phenylketonuria in newborns using bacterial inhibition test. In the nineties tandem mass spectrometry was established as the detection technique for phenylalanine and tyrosine. DBS became rapidly recognized for their clinical value: they were widely implemented in pediatric settings with mass spectrometric detection, and were closely associated to the debut of newborn screening (NBS) programs, as a part of public health policies. Since then, sample collection on paper cards has been explored with various analytical techniques in other areas more or less successfully regarding large-scale applications. Moreover, in the last 5 years a regain of interest for DBS was observed and originated from the bioanalytical community to support drug development (e.g., PK studies) or therapeutic drug monitoring mainly. Those recent applications were essentially driven by improved sensitivity of triple quadrupole mass spectrometers. This review presents an overall view of all instrumental and methodological developments for DBS analysis with mass spectrometric detection, with and without separation techniques. A general introduction to DBS will describe their advantages and historical aspects of their emergence. A second section will focus on blood collection, with a strong emphasis on specific parameters that can impact quantitative analysis, including chromatographic effects, hematocrit effects, blood effects, and analyte stability. A third part of the review is dedicated to sample preparation and will consider off-line and on-line extractions; in particular, instrumental designs that have been developed so far for DBS extraction will be detailed. Flow injection analysis and applications will be discussed in section IV. The application of surface analysis mass spectrometry (DESI, paper spray, DART, APTDCI, MALDI, LDTD-APCI, and ICP) to DBS is described in section V, while applications based on separation techniques (e.g., liquid or gas chromatography) are presented in section VI. To conclude this review, the current status of DBS analysis is summarized, and future perspectives are provided.
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Affiliation(s)
- Michel Wagner
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Life Sciences Mass Spectrometry, Quai Ernest-Ansermet 30, 1211, Geneva, Switzerland
| | - David Tonoli
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Life Sciences Mass Spectrometry, Quai Ernest-Ansermet 30, 1211, Geneva, Switzerland
| | - Emmanuel Varesio
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Life Sciences Mass Spectrometry, Quai Ernest-Ansermet 30, 1211, Geneva, Switzerland
| | - Gérard Hopfgartner
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Life Sciences Mass Spectrometry, Quai Ernest-Ansermet 30, 1211, Geneva, Switzerland
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Wilson K, Hawken S, Potter BK, Chakraborty P, Walker M, Ducharme R, Little J. Accurate prediction of gestational age using newborn screening analyte data. Am J Obstet Gynecol 2016; 214:513.e1-513.e9. [PMID: 26519781 DOI: 10.1016/j.ajog.2015.10.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 10/14/2015] [Accepted: 10/18/2015] [Indexed: 11/30/2022]
Abstract
BACKGROUND Identification of preterm births and accurate estimates of gestational age for newborn infants is vital to guide care. Unfortunately, in developing countries, it can be challenging to obtain estimates of gestational age. Routinely collected newborn infant screening metabolic analytes vary by gestational age and may be useful to estimate gestational age. OBJECTIVE We sought to develop an algorithm that could estimate gestational age at birth that is based on the analytes that are obtained from newborn infant screening. STUDY DESIGN We conducted a population-based cross-sectional study of all live births in the province of Ontario that included 249,700 infants who were born between April 2007 and March 2009 and who underwent newborn infant screening. We used multivariable linear and logistic regression analyses to build a model to predict gestational age using newborn infant screening metabolite measurements and readily available physical characteristics data (birthweight and sex). RESULTS The final model of our metabolic gestational dating algorithm had an average deviation between observed and expected gestational age of approximately 1 week, which suggests excellent predictive ability (adjusted R-square of 0.65; root mean square error, 1.06 weeks). Two-thirds of the gestational ages that were predicted by our model were accurate within ±1 week of the actual gestational age. Our logistic regression model was able to discriminate extremely well between term and increasingly premature categories of infants (c-statistic, >0.99). CONCLUSION Metabolic gestational dating is accurate for the prediction of gestational age and could have value in low resource settings.
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Affiliation(s)
- Kumanan Wilson
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada; School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
| | - Steven Hawken
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada; School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - Beth K Potter
- Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada; School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada; Newborn Screening Ontario, Ottawa, Ontario, Canada
| | - Pranesh Chakraborty
- Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; Newborn Screening Ontario, Ottawa, Ontario, Canada
| | - Mark Walker
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Obstetrics & Gynecology, University of Ottawa, Ottawa, Ontario, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - Robin Ducharme
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada
| | - Julian Little
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Hepatomegalie mit fokalen Läsionen und Nephromegalie bei einem Kleinkind. Monatsschr Kinderheilkd 2015. [DOI: 10.1007/s00112-015-3388-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Gemperle-Britschgi C, Iorgulescu D, Mager MA, Anton-Paduraru D, Vulturar R, Thöny B. A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population. Gene 2015; 576:182-8. [PMID: 26481238 DOI: 10.1016/j.gene.2015.10.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 06/02/2015] [Accepted: 10/12/2015] [Indexed: 10/22/2022]
Abstract
The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder.
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Affiliation(s)
- Corinne Gemperle-Britschgi
- Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Zürich, Switzerland
| | - Daniela Iorgulescu
- Center of Newborn Screening, Department of Pediatrics, Institute for Mother and Child Care, Bucharest, 120 Lacul Tei Blv., 020395, Romania
| | - Monica Alina Mager
- "I. Hatieganu" University of Medicine and Pharmacy - Cluj-Napoca, Department of Neurology, Romania
| | - Dana Anton-Paduraru
- "Gr.T.Popa" University of Medicine and Pharmacy, Newborn Screening Center Iasi, 3rd Clinic of Pediatrics, Romania
| | - Romana Vulturar
- "I.Hatieganu" University of Medicine and Pharmacy - Cluj-Napoca, Department of Molecular Sciences, Cluj-Napoca, Romania; Cognitive Neuroscience Laboratory, Babes-Bolyai University - Cluj-Napoca, Romania.
| | - Beat Thöny
- Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Zürich, Switzerland; Division of Metabolism, Department of Pediatrics, University of Zurich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland; Neuroscience Centre Zürich, University of Zürich, Zürich, Switzerland; Neuroscience Centre Zürich, ETH Zürich (ZNZ), Zürich, Switzerland; Children's Research Centre (CRC), Zürich, Switzerland.
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Abstract
BACKGROUND Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. This is an update of a previously published review. OBJECTIVES To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 08 June 2015. SELECTION CRITERIA Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population. DATA COLLECTION AND ANALYSIS No studies were identified for inclusion in the review. MAIN RESULTS No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.
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Affiliation(s)
- John H Walter
- Willink Biochemical Genetics Unit, Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Oxford Road, Manchester, UK, M13 9WL
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Hayeems RZ, Miller FA, Bombard Y, Avard D, Carroll J, Wilson B, Little J, Chakraborty P, Bytautas J, Giguere Y, Allanson J, Axler R. Expectations and values about expanded newborn screening: a public engagement study. Health Expect 2015; 18:419-29. [PMID: 23369110 PMCID: PMC5060787 DOI: 10.1111/hex.12047] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2012] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVES Newborn bloodspot screening (NBS) panels have expanded to include conditions for which treatment effects are less certain, creating debate about population-based screening criteria. We investigated Canadian public expectations and values regarding the types of conditions that should be included in NBS and whether parents should provide consent. METHODS Eight focus groups (FG; n = 60) included education, deliberative discussion and pre-/post-questionnaires. Data were analysed quantitatively and qualitatively. RESULTS Quantitatively, the majority supported NBS for serious disorders for which treatment is not available (95-98, 82%). A majority endorsed screening without explicit consent (77-88%) for treatable disorders, but 62% supported unpressured choice for screening for untreatable disorders. Qualitatively, participants valued treatment-related benefits for infants and informational benefits for families. Concern for anxiety, stigma and unwanted knowledge depended upon disease context and strength of countervailing benefits. CONCLUSIONS Anticipated benefits of expanded infant screening were prioritized over harms, with information provision perceived as a mechanism for mitigating harms and enabling choice. However, we urge caution around the potential for public enthusiasm to foster unlimited uptake of infant screening technologies.
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Affiliation(s)
- Robin Z Hayeems
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
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Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJC, Adams J. Current status of newborn screening worldwide: 2015. Semin Perinatol 2015; 39:171-87. [PMID: 25979780 DOI: 10.1053/j.semperi.2015.03.002] [Citation(s) in RCA: 395] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Newborn screening describes various tests that can occur during the first few hours or days of a newborn's life and have the potential for preventing severe health problems, including death. Newborn screening has evolved from a simple blood or urine screening test to a more comprehensive and complex screening system capable of detecting over 50 different conditions. While a number of papers have described various newborn screening activities around the world, including a series of papers in 2007, a comprehensive review of ongoing activities since that time has not been published. In this report, we divide the world into 5 regions (North America, Europe, Middle East and North Africa, Latin America, and Asia Pacific), assessing the current NBS situation in each region and reviewing activities that have taken place in recent years. We have also provided an extensive reference listing and summary of NBS and health data in tabular form.
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Affiliation(s)
- Bradford L Therrell
- National Newborn Screening and Genetics Resource Center (NNSGRC), Austin, TX; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX.
| | - Carmencita David Padilla
- College of Medicine, University of the Philippines Manila, Manila, Philippines; Newborn Screening Reference Center, National Institutes of Health (Philippines), Manila, Ermita, Philippines
| | - J Gerard Loeber
- International Society for Neonatal Screening, Bilthoven, Netherlands
| | - Issam Kneisser
- Newborn Screening Unit, Medical Genetic Unit, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Amal Saadallah
- Newborn Screening and Biochemical Genetics Laboratory, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Gustavo J C Borrajo
- Programa de Detección de Errores Congénitos, Fundación Bioquímica Argentina, La Plata, Argentina
| | - John Adams
- Canadian Organization for Rare Disorders, Toronto, Ontario, Canada
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Tal G, Pitt J, Morrisy S, Tzanakos N, Boneh A. An audit of newborn screening procedure: impact on infants presenting clinically before results are available. Mol Genet Metab 2015; 114:403-8. [PMID: 25604974 DOI: 10.1016/j.ymgme.2014.12.435] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 12/30/2014] [Accepted: 12/30/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVE Tandem mass spectrometry-based newborn screening (NBS) is a powerful screening tool. The NBS process includes sample collection, shipment, testing, analysis, reporting and communication with the infant's family. We explored the NBS programme-related factors that may delay diagnosis and may influence timely initiation of treatment in neonates who present before the screening results are available and therefore urgently need diagnosis and treatment. STUDY DESIGN Detailed retrospective review of all data regarding sampling, shipment, testing and notification, contact with family and initiation of treatment of all neonates with disorders of fatty acid oxidation (FAO) and protein metabolism (PM), who presented clinically before NBS results were available, between 1-February-2002 and 31-January-2014. RESULTS Of 847,418 newborns screened, 18 infants presented clinically before NBS results were available (FAO n = 9, median age 2.5 days; PM n = 9, median age 3 days). Samples were collected from 11 infants at age 48-72 h, as per instructions, and were received in the laboratory at a median age of 7 days (median 4 days from sample collection until receipt in the laboratory). Results were available within 24h in 16/18 infants. Treatment for a suspected metabolic disorder was initiated in seven infants before results were available. CONCLUSIONS An audit of the programme procedures enabled the identification of issues that can be improved. Some patients benefited from the availability of results shortly after presentation. Good communication between the laboratory, the clinical metabolic specialist service and the primary treating team ensures timely initiation of treatment in these infants.
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Affiliation(s)
- Galit Tal
- Metabolic Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Australia
| | - James Pitt
- Metabolic Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Sally Morrisy
- Metabolic Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Australia
| | - Nicholas Tzanakos
- Metabolic Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Australia
| | - Avihu Boneh
- Metabolic Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
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24
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Nicholls SG, Tessier L, Etchegary H, Brehaut JC, Potter BK, Hayeems RZ, Chakraborty P, Marcadier J, Milburn J, Pullman D, Turner L, Wilson BJ. Stakeholder attitudes towards the role and application of informed consent for newborn bloodspot screening: a study protocol. BMJ Open 2014; 4:e006782. [PMID: 25421341 PMCID: PMC4244491 DOI: 10.1136/bmjopen-2014-006782] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION Newborn bloodspot screening (NBS) involves testing a small sample of blood taken from the heel of the newborn for a number of serious and life-limiting conditions. In Canada, newborn screening programmes fall under provincial and territorial jurisdiction with no federal coordination. To date, we know very little about the underlying beliefs around different consent practices or how terminology is interpreted by different individuals. Differences in attitudes may have important healthcare consequences. This study will provide empirical data comparing stakeholder opinions on their understanding of consent-related terminology, the perceived applicability of different consent approaches to newborn screening, and the requirements of these different approaches. METHODS AND ANALYSIS Parents, healthcare professionals and policymakers will be recruited in the provinces of Ontario and Newfoundland and Labrador. Parents will be identified through records held by each provincial screening programme. Healthcare professionals will be purposively sampled on the basis of engagement with newborn screening. Within each province we will identify policymakers who have policy analysis or advisory responsibilities relating to NBS. Data collection will be by qualitative interviews. We will conduct 20 interviews with parents of young children, 10 interviews with key healthcare professionals across the range of appropriate specialties and 10 with policymakers at each site (40 per site, total, N=80). The examination of the transcripts will follow a thematic analysis approach. Recruitment started in June 2014 and is expected to be complete by June 2015. ETHICS AND DISSEMINATION This study received ethics approval from the Ottawa Health Science Network Research Ethics Board, the Children's Hospital of Eastern Ontario Research Ethics Board (both Ontario), and the Health Research Ethics Authority (Newfoundland and Labrador). RESULTS These will be reported in peer-reviewed publications and conference presentations. The results will have specific application to the development of parent education materials for newborn screening.
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Affiliation(s)
- S G Nicholls
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - L Tessier
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - H Etchegary
- Clinical Epidemiology, Memorial University, St. John's, Newfoundland and Labrador, Canada
| | - J C Brehaut
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada
| | - B K Potter
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - R Z Hayeems
- Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
- Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Canada
| | - P Chakraborty
- Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO), Ottawa, Ontario, Canada
| | - J Marcadier
- Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO), Ottawa, Ontario, Canada
| | - J Milburn
- Better Outcomes Registry and Network (BORN), Children's Hospital of Eastern Ontario (CHEO), Ottawa, Ontario, Canada
| | - D Pullman
- Faculty of Medicine, Memorial University, St. Johns, Newfoundland and Labrador, Canada
| | - L Turner
- Eastern Health, St. John's, Newfoundland and Labrador, Canada
| | - B J Wilson
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
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25
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Diagnosis of cystathionine beta-synthase deficiency by genetic analysis. J Neurol Sci 2014; 347:305-9. [PMID: 25455305 DOI: 10.1016/j.jns.2014.10.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 10/14/2014] [Accepted: 10/16/2014] [Indexed: 12/14/2022]
Abstract
Intellectual disability like other common diseases is often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. We present diagnosis of cystathionine beta-synthase (CBS) deficiency in a multiply affected Iranian family with obvious intellectual disability based on whole genome SNP homozygosity mapping. Diagnosis based on clinical presentations had not been made because of unavailability of appropriate medical services. Genetic analysis led to identification of homozygous c.346G>A in CBS that causes p.Gly116Arg in the encoded protein, cystathionine beta-synthase. CBS is the most common causative gene of homocystinurea. Later, the same mutation was found in three other apparently unrelated Iranian homocystinuria patients. p.Gly116Arg was reported once before in a Turkish patient, suggesting it may be a common CBS deficiency causing mutation in the Middle East. Clinical features of the patients are reported that evidence to variable presentations caused by the same mutation. Finally, observations in heterozygous carriers of the mutation suggest data that a single allele of the p.Gly116Arg causing mutation may have phenotypic consequences, including cardiac related phenotypes. Our study attests to the powers of genetic analysis for diagnosis especially for some forms of intellectual disability, with known genetic causing agents.
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26
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Shackley P, Dixon S. The random card sort method and respondent certainty in contingent valuation: an exploratory investigation of range bias. HEALTH ECONOMICS 2014; 23:1213-23. [PMID: 23922327 DOI: 10.1002/hec.2980] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 05/07/2013] [Accepted: 07/04/2013] [Indexed: 05/07/2023]
Abstract
Willingness to pay (WTP) values derived from contingent valuation surveys are prone to a number of biases. Range bias occurs when the range of money values presented to respondents in a payment card affects their stated WTP values. This paper reports the results of an exploratory study whose aim was to investigate whether the effects of range bias can be reduced through the use of an alternative to the standard payment card method, namely, a random card sort method. The results suggest that the random card sort method is prone to range bias but that this bias may be mitigated by restricting the analysis to the WTP values of those respondents who indicate they are 'definitely sure' they would pay their stated WTP.
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Affiliation(s)
- Phil Shackley
- School of Health and Related Research, University of Sheffield, Sheffield, UK
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27
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Nicholls SG, Wilson BJ, Etchegary H, Brehaut JC, Potter BK, Hayeems R, Chakraborty P, Milburn J, Pullman D, Turner L, Carroll JC. Benefits and burdens of newborn screening: public understanding and decision-making. Per Med 2014; 11:593-607. [PMID: 29758802 DOI: 10.2217/pme.14.46] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In this article we review the literature regarding the public understanding of the potential benefits and burdens of expanded newborn bloodspot screening. We draw attention to broadened notions of benefit that go beyond early identification of asymptomatic individuals and interventions to reduce morbidity or mortality, and include benefits gained by families through knowledge that may facilitate life choices, as well as gains generated by avoiding diagnostic delays. We also reflect on burdens such as increasing false-positive results and parental anxiety, together with risks of overdiagnosis when the natural history of a condition is poorly understood. We conclude that expanded notions of benefit and burden bring with them implications for parental consent and confidentiality and the secondary use of bloodspots.
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Affiliation(s)
- Stuart G Nicholls
- Department of Epidemiology & Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Brenda J Wilson
- Department of Epidemiology & Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Holly Etchegary
- Clinical Epidemiology, Memorial University, St John's, Newfoundland and Labrador, Canada
| | - Jamie C Brehaut
- Department of Epidemiology & Community Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Centre for Practice Changing Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Beth K Potter
- Department of Epidemiology & Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Robin Hayeems
- Hospital for Sick Children Research Institute, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada.,Institute of Health Policy Management & Evaluation, University of Toronto, Canada
| | - Pranesh Chakraborty
- Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO), Ottawa, Ontario, Canada
| | - Jennifer Milburn
- Better Outcomes Registry & Network (BORN), Children's Hospital of Eastern Ontario (CHEO), Ottawa, Ontario, Canada
| | - Daryl Pullman
- Faculty of Medicine, Memorial University, St Johns, Newfoundland & Labrador, Canada
| | - Lesley Turner
- Eastern Health, St John's, Newfoundland & Labrador, Canada
| | - June C Carroll
- Department of Family & Community Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada
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28
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Mak CM, Lee HCH, Chan AYW, Lam CW. Inborn errors of metabolism and expanded newborn screening: review and update. Crit Rev Clin Lab Sci 2014; 50:142-62. [PMID: 24295058 DOI: 10.3109/10408363.2013.847896] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.
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Affiliation(s)
- Chloe Miu Mak
- Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital , Hong Kong, SAR , China and
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29
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Abstract
Hypoglycemia in the pediatric population is a common finding important to recognize and manage to prevent brain injury. Recent advances in molecular genetics have provided new insight into its biochemical and physiologic basis and have led to more appropriate and specific treatment. Although a major cause of brain injury in pediatrics, the ability to predict the long-term outcome in these patients remains difficult. Identification of these at-risk individuals is important. The physiologic adaptations associated with transition from fetal to neonatal life are now better understood thus allowing for improved surveillance and management. Despite these advances, analytical limitations of point-of-care testing instruments at low glucose concentration continue to persist, This review aims to address these questions and provide an overview of pediatric hypoglycemia and the molecular pathways involved.
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30
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Fischer KE, Rogowski WH. Funding decisions for newborn screening: a comparative review of 22 decision processes in Europe. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2014; 11:5403-30. [PMID: 24852389 PMCID: PMC4053875 DOI: 10.3390/ijerph110505403] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 04/29/2014] [Accepted: 05/09/2014] [Indexed: 11/30/2022]
Abstract
Decision-makers need to make choices to improve public health. Population-based newborn screening (NBS) is considered as one strategy to prevent adverse health outcomes and address rare disease patients' needs. The aim of this study was to describe key characteristics of decisions for funding new NBS programmes in Europe. We analysed past decisions using a conceptual framework. It incorporates indicators that capture the steps of decision processes by health care payers. Based on an internet survey, we compared 22 decisions for which answers among two respondents were validated for each observation. The frequencies of indicators were calculated to elicit key characteristics. All decisions resulted in positive, mostly unrestricted funding. Stakeholder participation was diverse focusing on information provision or voting. Often, decisions were not fully transparent. Assessment of NBS technologies concentrated on expert opinion, literature review and rough cost estimates. Most important appraisal criteria were effectiveness (i.e., health gain from testing for the children being screened), disease severity and availability of treatments. Some common and diverging key characteristics were identified. Although no evidence of explicit healthcare rationing was found, processes may be improved in respect of transparency and scientific rigour of assessment.
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Affiliation(s)
| | - Wolf Henning Rogowski
- Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Health Economics and Health Care Management, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
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31
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la Marca G. Mass spectrometry in clinical chemistry: the case of newborn screening. J Pharm Biomed Anal 2014; 101:174-82. [PMID: 24844843 DOI: 10.1016/j.jpba.2014.03.047] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 03/28/2014] [Indexed: 12/13/2022]
Abstract
Newborn screening (NBS) program is a complex and organized system consisting of family and personnel education, biochemical tests, confirmatory biochemical and genetic tests, diagnosis, therapy, and patient follow up. The program identifies treatable metabolic disorders possibly when asymptomatic by using dried blood spot (DBS). During the last 20 years tandem mass spectrometry (TMS) has become the leading technology in NBS programs demonstrating to be versatile, sensitive and specific. There is consistent evidence of benefits from NBS for many disorders detected by TMS as well as for congenital hypothyroidism, cystic fibrosis, congenital adrenal hyperplasia by immune-enzymatic methods. Real time PCR tests have more recently been proposed for the detection of some severe combined immunodeficiences (SCID) along with the use of TMS for ADA and PNP SCID; a first evaluation of their cost-benefit ratio is still ongoing. Avoiding false negative results by using specific biomarkers and reducing the false positive rate by using second tier tests, is fundamental for a successful NBS program. The fully integration of NBS and diagnostic laboratories with clinical service is crucial to have the best effectiveness in a comprehensive NBS system.
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Affiliation(s)
- Giancarlo la Marca
- Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Newborn Screening, Biochemistry and Pharmacology laboratory, Meyer Children's University Hospital, Florence, Italy.
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Isabel IG, Cynthia FL, Diana RG, Leticia BM, Sara GL, Susana MS, Marcela VA. Inborn Errors of Intermediary Metabolism in Critically Ill Mexican Newborns. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2014. [DOI: 10.1177/2326409814529649] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Ibarra-González Isabel
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Fernández-Lainez Cynthia
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Reyes-González Diana
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Belmont-Martínez Leticia
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Guillén-López Sara
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Monroy-Santoyo Susana
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Vela-Amieva Marcela
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
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Nicholls SG, Southern KW. Considering consent: a structural equation modelling analysis of factors influencing decisional quality when accepting newborn screening. J Inherit Metab Dis 2014; 37:197-205. [PMID: 24043381 DOI: 10.1007/s10545-013-9651-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 08/09/2013] [Accepted: 08/20/2013] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Newborn bloodspot screening (NBS) programs generate an ethical tension between promoting the uptake of effective public health measures and facilitating informed consent from individuals. AIM To explore the factors that affect parental perceptions of decision quality when accepting NBS METHODS: Survey of parents with children screened in 2008 (n = 154, 32% response rate). Questions were based on previous research and existing measures. The primary outcome was decision quality. Predictors were latent constructs of Attitudes to medicine, Perceived knowledge, Attitudes to screening, and Perceived choice. Responses were analysed using structural equation modelling. RESULTS Increases in perceived choice and positive attitudes towards screening improved decision quality. Perceived knowledge had a significant and positive relationship with attitudes to screening (0.375, p < 0.01) as did perceived choice on perceived knowledge (0.806, p < 0.01). Attitudes to screening were also significantly influenced by attitudes to medicine, although less so than the effect of perceived knowledge. The model had good fit on all indices (χ(2) = 61.396, df = 48, p = 0.093; CFI = 0.979; RMSEA = 0.043). CONCLUSIONS Our results implicate the presentation of screening as a key determinant of decision quality both in terms of the immediate information regarding the potential benefits and risks, but also the way in which consent processes are managed. If we want to better understand parent decision-making we need to go beyond analyses of information content, or parental recall of this, but consider the context in which screening is provided.
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Affiliation(s)
- Stuart G Nicholls
- Department of Epidemiology and Community Medicine, University of Ottawa, K1H 8M5, Ottawa, Canada,
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34
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Wilson K, Hawken S, Ducharme R, Potter BK, Little J, Thébaud B, Chakraborty P. Metabolomics of prematurity: analysis of patterns of amino acids, enzymes, and endocrine markers by categories of gestational age. Pediatr Res 2014; 75:367-73. [PMID: 24216540 DOI: 10.1038/pr.2013.212] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 06/24/2013] [Indexed: 11/09/2022]
Abstract
BACKGROUND Prematurity may influence the levels of amino acids, enzymes, and endocrine markers obtained through newborn screening. Identifying which analytes are the most affected by degree of prematurity could provide insight into how prematurity impacts metabolism. METHODS Analytes from blood spots assayed by Newborn Screening Ontario between March 2006 and April 2009 were used in this analysis. We examined the associations between the degree of prematurity and the levels of amino acids, enzymes, and endocrine markers in all newborns with and without adjustment for birth weight, feeding status, sample timing, transfusion, and sex. RESULTS Our analysis included the following cohorts: 373,819 children born at term (>36 wk gestation), 26,483 near-term children (33-36 wk gestation), 4,354 very premature children (28-32 wk gestation), and 1,146 extremely premature children (<28 wk gestation). Of the amino acids showing consistent trends across categories of prematurity, the levels of three amino acids (arginine, leucine, and valine) were at least 50% different between the cohorts of extremely premature and term children. The levels of 17-hydroxyprogesterone increased with increasing prematurity, while thyrotropin-stimulating hormone values consistently decreased with increasing prematurity. None of the three enzyme markers we examined showed a trend in levels across categories of prematurity. CONCLUSION This study demonstrates that children at different stages of prematurity are metabolically distinct. Future research should focus on the mechanism by which specific analytes are influenced by prematurity.
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Affiliation(s)
- Kumanan Wilson
- 1] Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada [2] Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada [3] Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Steven Hawken
- 1] Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada [2] Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada [3] Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Robin Ducharme
- 1] Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada [2] Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada [3] Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Beth K Potter
- 1] Institute for Clinical Evaluative Sciences, University of Ottawa, Ottawa, Ontario, Canada [2] Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada [3] Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Julian Little
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Bernard Thébaud
- 1] Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada [2] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada [3] Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - Pranesh Chakraborty
- 1] Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada [2] Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
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Tezel B, Dilli D, Bolat H, Şahman H, Özbaş S, Acıcan D, Ertek M, Köse MR, Dilmen U. The development and organization of newborn screening programs in Turkey. J Clin Lab Anal 2014; 28:63-9. [PMID: 24375520 PMCID: PMC6807568 DOI: 10.1002/jcla.21645] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 06/03/2013] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Newborn screening tests have been designed to identify infants with severe disorders that are relatively prevalent and treatable or controllable. Comparing to other countries, the incidence of these diseases are very high in Turkey where the rate of consanguineous marriage is high. METHODS In this article, it is aimed to evaluate the development and organization of newborn screening programs in Turkey which include phenylketonuria, congenital hypothyroidism and biotinidase deficiency screenings. The point reached today, limitations of the program, expectations and projects for the future are discussed. RESULTS Today, the point reached in screening programs of the country is appreciable. While the screening rate of the live born babies was 4,7% in 1987, this rate reached to 95% by 2008. Predicted target for newborn screening program at the strategic plan of Ministry of Health for 2010-2014 was to enhance this rate above 95% by the end of 2012. It seems that the envisaged goal has been reached. CONCLUSION National newborn screening program appears to be conducted successfully and extensively as a result of political determination and performance of health care workers who are in charge of this program. Nevertheless, limited numbers of the nutrition and metabolism clinics and specialists on these branches have caused some access difficulties, waste of time, and financial loss. Therefore, special planning to improve quality and the number of the clinics would be useful.
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Affiliation(s)
- Başak Tezel
- Department of Child and Adolescent HealthPublic Health Institution of TurkeyAnkaraTurkey
| | - Dilek Dilli
- Department of NeonatologyDr Sami Ulus Maternity and Children Research and Training HospitalAnkaraTurkey
| | - Hilal Bolat
- Department of Child and Adolescent HealthPublic Health Institution of TurkeyAnkaraTurkey
| | - Hatice Şahman
- Department of Child and Adolescent HealthPublic Health Institution of TurkeyAnkaraTurkey
| | - Sema Özbaş
- Department of Child and Adolescent HealthPublic Health Institution of TurkeyAnkaraTurkey
| | - Deniz Acıcan
- Department of Child and Adolescent HealthPublic Health Institution of TurkeyAnkaraTurkey
| | - Mustafa Ertek
- Hospital ManagerDr Abdurrahman Yurtaslan Oncology Training and Research HospitalAnkaraTurkey
| | - Mehmet Rıfat Köse
- Advisor to Minister, Member of Health Policy BoardMinistry of HealthAnkaraTurkey
| | - Uğur Dilmen
- Department of Pediatrics and NeonatologyYıldırım Beyazıt University Faculty of MedicineAnkaraTurkey
- Director General of Health ResearchMinistry of HealthAnkaraTurkey
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Abstract
BACKGROUND Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. OBJECTIVES To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 15 May 2013. SELECTION CRITERIA Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population. DATA COLLECTION AND ANALYSIS No studies were identified for inclusion in the review. MAIN RESULTS No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.
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Affiliation(s)
- John H Walter
- Willink Biochemical Genetics Unit, Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Oxford Road, Manchester, UK, M13 9WL
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Chen WH, Hsieh SL, Hsu KP, Chen HP, Su XY, Tseng YJ, Chien YH, Hwu WL, Lai F. Web-based newborn screening system for metabolic diseases: machine learning versus clinicians. J Med Internet Res 2013; 15:e98. [PMID: 23702487 PMCID: PMC3668606 DOI: 10.2196/jmir.2495] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Revised: 03/04/2013] [Accepted: 04/07/2013] [Indexed: 01/06/2023] Open
Abstract
Background A hospital information system (HIS) that integrates screening data and interpretation of the data is routinely requested by hospitals and parents. However, the accuracy of disease classification may be low because of the disease characteristics and the analytes used for classification. Objective The objective of this study is to describe a system that enhanced the neonatal screening system of the Newborn Screening Center at the National Taiwan University Hospital. The system was designed and deployed according to a service-oriented architecture (SOA) framework under the Web services .NET environment. The system consists of sample collection, testing, diagnosis, evaluation, treatment, and follow-up services among collaborating hospitals. To improve the accuracy of newborn screening, machine learning and optimal feature selection mechanisms were investigated for screening newborns for inborn errors of metabolism. Methods The framework of the Newborn Screening Hospital Information System (NSHIS) used the embedded Health Level Seven (HL7) standards for data exchanges among heterogeneous platforms integrated by Web services in the C# language. In this study, machine learning classification was used to predict phenylketonuria (PKU), hypermethioninemia, and 3-methylcrotonyl-CoA-carboxylase (3-MCC) deficiency. The classification methods used 347,312 newborn dried blood samples collected at the Center between 2006 and 2011. Of these, 220 newborns had values over the diagnostic cutoffs (positive cases) and 1557 had values that were over the screening cutoffs but did not meet the diagnostic cutoffs (suspected cases). The original 35 analytes and the manifested features were ranked based on F score, then combinations of the top 20 ranked features were selected as input features to support vector machine (SVM) classifiers to obtain optimal feature sets. These feature sets were tested using 5-fold cross-validation and optimal models were generated. The datasets collected in year 2011 were used as predicting cases. Results The feature selection strategies were implemented and the optimal markers for PKU, hypermethioninemia, and 3-MCC deficiency were obtained. The results of the machine learning approach were compared with the cutoff scheme. The number of the false positive cases were reduced from 21 to 2 for PKU, from 30 to 10 for hypermethioninemia, and 209 to 46 for 3-MCC deficiency. Conclusions This SOA Web service–based newborn screening system can accelerate screening procedures effectively and efficiently. An SVM learning methodology for PKU, hypermethioninemia, and 3-MCC deficiency metabolic diseases classification, including optimal feature selection strategies, is presented. By adopting the results of this study, the number of suspected cases could be reduced dramatically.
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Affiliation(s)
- Wei-Hsin Chen
- National Taiwan University, Graduate Institute of Biomedical Electronics and Bioinformatics, Taipei, Taiwan
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Cribado neonatal ampliado en la Región de Murcia. Experiencia de tres años. Med Clin (Barc) 2012; 139:566-71. [DOI: 10.1016/j.medcli.2011.10.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Revised: 10/07/2011] [Accepted: 10/11/2011] [Indexed: 11/23/2022]
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Newborn screening and renal disease: where we have been; where we are now; where we are going. Pediatr Nephrol 2012; 27:1453-64. [PMID: 21947256 DOI: 10.1007/s00467-011-1995-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 07/22/2011] [Accepted: 08/12/2011] [Indexed: 10/17/2022]
Abstract
Newborn screening (NBS) has rapidly changed since its origins in the 1960s. Beginning with a single condition, then a handful in the 1990 s, NBS has expanded in the past decade to allow the detection of many disorders of amino-acid, organic-acid, and fatty-acid metabolism. These conditions often present with recurrent acute attacks of metabolic acidosis, hypoglycemia, liver failure, and hyperammonemia that may be prevented with initiation of early treatment. Renal disease is an important component of these disorders and is a frequent source of morbidity. Hemodialysis is often required for hyperammonemia in the organic acidemias and urea-cycle disorders. Rhabdomyolysis with renal failure is a frequent complication in fatty-acid oxidation disorders. Newer screening methods are under investigation to detect lysosomal storage diseases, primary immunodeficiencies, and primary renal disorders. These advances will present many challenges to nephrologists and pediatricians with respect to closely monitoring and caring for children with such disorders.
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Loeber JG, Burgard P, Cornel MC, Rigter T, Weinreich SS, Rupp K, Hoffmann GF, Vittozzi L. Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1. From blood spot to screening result. J Inherit Metab Dis 2012; 35:603-11. [PMID: 22552820 DOI: 10.1007/s10545-012-9483-0] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 03/13/2012] [Accepted: 03/28/2012] [Indexed: 11/26/2022]
Abstract
In many European countries neonatal screening has been introduced over the last 50 years as an important public health programme. Depending on health care structure, available funds, local politics, input from professional groups, parent groups, and the general public this introduction has led to different approaches in the way the screening programmes have been set up, financed and governed. To get some insight about the current situation, in 2009 the European Union, via its EAHC agency, put out a call for a tender that was acquired by our project group. An online survey was compiled in which the whole screening programme was covered by a questionnaire. This survey covered the EU member states, (potential) candidate member states and EFTA countries, in total 40 countries. Results showed little consensus concerning 1. information of parents including informed consent; 2. which conditions are screened for, ranging from 1 to around 30 conditions; 3. sampling time post partum; 4. screening methodology including cut-offs values even between screening laboratories within countries.; 5. storage of residual specimens, varying from 3 months to 1000 years. In addition, confirmatory diagnostics and follow-up also show large discrepancies (Burgard et al. http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64 2011). In addition to the current practices report an expert opinion document has been produced with recommendations to the EU Commission for future improvements, e.g. in parallel to the way the USA has harmonized its practices based on recommendations by the American College of Medical Genetics (Watson et al., Pediatrics 117: S296-S307, 2006).
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Affiliation(s)
- J Gerard Loeber
- National Institute for Public Health (RIVM), P.O. Box 1, 3720BA, Bilthoven, The Netherlands.
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Hamers FF, Rumeau-Pichon C. Cost-effectiveness analysis of universal newborn screening for medium chain acyl-CoA dehydrogenase deficiency in France. BMC Pediatr 2012; 12:60. [PMID: 22681855 PMCID: PMC3464722 DOI: 10.1186/1471-2431-12-60] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 06/08/2012] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Five diseases are currently screened on dried blood spots in France through the national newborn screening programme. Tandem mass spectrometry (MS/MS) is a technology that is increasingly used to screen newborns for an increasing number of hereditary metabolic diseases. Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is among these diseases. We sought to evaluate the cost-effectiveness of introducing MCADD screening in France. METHODS We developed a decision model to evaluate, from a societal perspective and a lifetime horizon, the cost-effectiveness of expanding the French newborn screening programme to include MCADD. Published and, where available, routine data sources were used. Both costs and health consequences were discounted at an annual rate of 4%. The model was applied to a French birth cohort. One-way sensitivity analyses and worst-case scenario simulation were performed. RESULTS We estimate that MCADD newborn screening in France would prevent each year five deaths and the occurrence of neurological sequelae in two children under 5 years, resulting in a gain of 128 life years or 138 quality-adjusted life years (QALY). The incremental cost per year is estimated at €2.5 million, down to €1 million if this expansion is combined with a replacement of the technology currently used for phenylketonuria screening by MS/MS. The resulting incremental cost-effectiveness ratio (ICER) is estimated at €7 580/QALY. Sensitivity analyses indicate that while the results are robust to variations in the parameters, the model is most sensitive to the cost of neurological sequelae, MCADD prevalence, screening effectiveness and screening test cost. The worst-case scenario suggests an ICER of €72 000/QALY gained. CONCLUSIONS Although France has not defined any threshold for judging whether the implementation of a health intervention is an efficient allocation of public resources, we conclude that the expansion of the French newborn screening programme to MCADD would appear to be cost-effective. The results of this analysis have been used to produce recommendations for the introduction of universal newborn screening for MCADD in France.
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Affiliation(s)
- Françoise F Hamers
- Department of Economic and Public Health Evaluation, Haute Autorité de Santé (HAS), 2 avenue du Stade de France, Saint-Denis, France
| | - Catherine Rumeau-Pichon
- Department of Economic and Public Health Evaluation, Haute Autorité de Santé (HAS), 2 avenue du Stade de France, Saint-Denis, France
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Stove CP, Ingels ASM, De Kesel PM, Lambert WE. Dried blood spots in toxicology: from the cradle to the grave? Crit Rev Toxicol 2012; 42:230-43. [DOI: 10.3109/10408444.2011.650790] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Abstract
The advent of tandem mass spectrometry (MS/MS) around 10 years ago allowed to enlarge consistently the spectrum of metabolic diseases that might be easily and quickly detected. MS/MS was applied to newborn screening in many developed countries, with a wide use, to detect as many as 55 abnormal biochemical conditions (USA), or a restricted one detecting only few diseases (Germany, UK, and Switzerland). Many factors were probably contributing to these very different health organization policies. Although neonatal screening is widely considered extremely useful and efficacious to improve prognosis of many metabolic disorders, the statistically significant demonstration of benefit is quite hard to reach for reasons mainly incidental to the characteristics of these disorders. The expanded newborn screening, in its wide application, includes at present severe diseases presenting in the first days of life, diseases for which treatment is not available, conditions with uncertain significance which are probably not diseases, detection of metabolic disturbances of the mother and all the mildest forms of organic acidurias, urea cycle disorders, fatty acid beta-oxidation defects that may have the possibility to remain asymptomatic for the whole life or may have an acute life-threatening onset of the disease many years later. Which could be the better approach to newborn screening is not clear at present, and probably, it will not be the same for each country. Results of regional screening programs need to be carefully collected and analyzed in future years, with the aim to optimize screening practice in the different countries. Efforts should also be addressed to improve screening programs in the developing countries.
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Affiliation(s)
- Rossella Parini
- Rare Metabolic Diseases Unit, Pediatric Clinic, San Gerardo Hospital, University Milano Bicocca, Monza, Italy.
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Grünert SC, Müllerleile S, de Silva L, Barth M, Walter M, Walter K, Meissner T, Lindner M, Ensenauer R, Santer R, Bodamer OA, Baumgartner MR, Brunner-Krainz M, Karall D, Haase C, Knerr I, Marquardt T, Hennermann JB, Steinfeld R, Beblo S, Koch HG, Konstantopoulou V, Scholl-Bürgi S, van Teeffelen-Heithoff A, Suormala T, Sperl W, Kraus JP, Superti-Furga A, Schwab KO, Sass JO. Propionic acidemia: neonatal versus selective metabolic screening. J Inherit Metab Dis 2012; 35:41-9. [PMID: 22134541 DOI: 10.1007/s10545-011-9419-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 10/08/2011] [Accepted: 10/17/2011] [Indexed: 11/29/2022]
Abstract
BACKGROUND Whereas propionic acidemia (PA) is a target disease of newborn screening (NBS) in many countries, it is not in others. Data on the benefit of NBS for PA are sparse. STUDY DESIGN Twenty PA patients diagnosed through NBS were compared to 35 patients diagnosed by selective metabolic screening (SMS) prompted by clinical findings, family history, or routine laboratory test results. Clinical and biochemical data of patients from 16 metabolic centers in Germany, Austria, and Switzerland were evaluated retrospectively. Additionally, assessment of the intelligent quotient (IQ) was performed. In a second step, the number of PA patients who have died within the past 20 years was estimated based on information provided by the participating metabolic centers. RESULTS Patients diagnosed through NBS had neither a milder clinical course regarding the number of metabolic crises nor a better neurological outcome. Among NBS patients, 63% were already symptomatic at the time of diagnosis, and <10% of all patients remained asymptomatic. Among all PA patients, 76% were found to be at least mildly mentally retarded, with an IQ <69. IQ was negatively correlated with the number of metabolic decompensations, but not simply with the patients' age. Physical development was also impaired in the majority of patients. Mortality rates tended to be lower in NBS patients compared with patients diagnosed by SMS. CONCLUSION Early diagnosis of PA through NBS seems to be associated with a lower mortality rate. However, no significant benefit could be shown for surviving patients with regard to their clinical course, including the number of metabolic crises, physical and neurocognitive development, and long-term complications.
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Affiliation(s)
- S C Grünert
- Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Freiburg, Freiburg, Germany
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Dixon S, Shackley P, Bonham J, Ibbotson R. Putting a value on the avoidance of false positive results when screening for inherited metabolic disease in the newborn. J Inherit Metab Dis 2012; 35:169-76. [PMID: 21617925 DOI: 10.1007/s10545-011-9354-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Revised: 05/16/2011] [Accepted: 05/18/2011] [Indexed: 10/18/2022]
Abstract
Despite the increase in the number of inherited metabolic diseases that can be detected at birth using a single dried blood spot sample, the impact of false positive results on parents remains a concern. We used an economic approach - the contingent valuation method - which asks parents to give their maximum willingness to pay for an extension in a screening programme and the degree to which the potential for false positive results diminishes their valuations. 160 parents of a child or children under the age of 16 years were surveyed and given descriptions of the current screening programme in the UK, an extended programme and an extended programme with no false positives. 148 (92.5%) respondents said they would accept the screen for the five extra conditions in an expanded screening programme whilst 10 (6.3%) said they would not and two were unsure. When asked to indicate if they would choose to be screened under an expanded screening programme with no false positive results, 152 (95%) said they would, five (3.1%) said they would not, two were unsure, and there was one non-response. 151 (94.4%) said they preferred the hypothetical test with no false-positives. The mean willingness to pay for the expanded programme was £178 compared to £219 for the hypothetical expanded programme without false positives (p > 0.05). The results suggest that there is widespread parental support for extended screening in the UK and that the number of false-positives is a relatively small issue.
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Affiliation(s)
- Simon Dixon
- School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield S1 4DA, UK.
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Oerton J, Khalid JM, Besley G, Dalton RN, Downing M, Green A, Henderson M, Krywawych S, Leonard J, Andresen BS, Dezateux C. Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: prevalence, predictive value and test validity based on 1.5 million screened babies. J Med Screen 2011; 18:173-81. [PMID: 22166308 PMCID: PMC3243649 DOI: 10.1258/jms.2011.011086] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain. OBJECTIVE To estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance. SETTING All births in areas of high ethnic minority prevalence in England. METHODS Prospective multicentre pilot screening service; testing at age five to eight days; standardized screening, diagnostic and management protocols; independent expert review of screen-positive cases to assign MCADD diagnosis and predicted clinical importance (definite or uncertain). RESULTS Approximately 1.5 million babies (79% white; 10% Asian) were screened. MCADD was confirmed in 147 of 190 babies with a positive screening result (screen-positive prevalence: 1.20 per 10,000; MCADD prevalence: 0.94 per 10,000; PPV 77% [95% CI 71-83]), comprising 103 (70%) with MCADD variants of definite clinical importance (95 white [95%]; 2 Asian [2%]) and 44 (30%) with variants of uncertain clinical importance (29 white [67%]; 12 Asian [28%]). CONCLUSION One baby in every 10,000 born in England is diagnosed with MCADD by newborn screening; around 60 babies each year. While the majority of MCADD variants detected are predicted to be of definite clinical importance, this varies according to ethnic group, with variants of uncertain importance most commonly found in Asian babies. These findings provide support for MCADD screening but highlight the need to take account of the ethnic diversity of the population tested at implementation.
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Affiliation(s)
- Juliet Oerton
- MRC Centre of Epidemiology for Child Health, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, United Kingdom
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Couce ML, Castiñeiras DE, Bóveda MD, Baña A, Cocho JA, Iglesias AJ, Colón C, Alonso-Fernández JR, Fraga JM. Evaluation and long-term follow-up of infants with inborn errors of metabolism identified in an expanded screening programme. Mol Genet Metab 2011; 104:470-5. [PMID: 22000754 DOI: 10.1016/j.ymgme.2011.09.021] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 09/15/2011] [Accepted: 09/16/2011] [Indexed: 11/18/2022]
Abstract
Newborn screening (NBS) by tandem mass spectrometry started in Galicia (Spain) in 2000. We analyse the results of screening and clinical follow-up of inborn errors of metabolism (IEM) detected during 10 years. Our programme basically includes the disorders recommended by the American College of Medical Genetics. Since 2002, blood and urine samples have been collected from every newborn on the 3rd day of life; before then, samples were collected between the 5th and 8th days. Newborns who show abnormal results are referred to the clinical unit for diagnosis and treatment. In these 10 years, NBS has led directly to the identification of 137 IEM cases (one per 2060 newborns, if 35 cases of benign hyperphenylalaninemia are excluded). In addition, 33 false positive results and 10 cases of transitory elevation of biomarkers were identified (making the positive predictive rate 76.11%), and 4 false negative results. The use of urine samples contributed significantly to IEM detection in 44% of cases. Clinical symptoms appeared before positive screening results in nine patients (6.6%), four of them screened between days 5 and 8. The death rate was 2.92%; of the survivors, 95.5% were asymptomatic after a mean observation period of 54 months, and only two had an intellectual/psychomotor development score less than 85. Compared to other studies, a high incidence of type I glutaric aciduria was detected, one in 35,027 newborns. This report highlights the benefits of urine sample collection during screening, and it is the first study on expanded newborn screening results in Spain.
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Affiliation(s)
- Ma Luz Couce
- Unidad de Diagnóstico y Tratamiento de Enfermedades Metabólicas Congénitas, Departamento de Pediatría, Hospital Clínico Universitario de Santiago, Spain.
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Abstract
BACKGROUND Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. OBJECTIVES To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. SEARCH STRATEGY We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 27 June 2011. SELECTION CRITERIA Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population. DATA COLLECTION AND ANALYSIS No studies were identified for inclusion in the review. MAIN RESULTS No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.
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Affiliation(s)
- John H Walter
- Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Pendlebury, Manchester, UK, M27 4HA
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Abstract
Identification and investigation of hypoglycaemia in childhood remains an important clinical emergency. Rapid recognition and appropriate management of this clinical state continues to be important in order to prevent neurological damage or even death. The purpose of this review is to provide an update on the advances made in this area since the review by Bonham in this journal in 1993. Advances in molecular science and diagnostic techniques have assisted in understanding the mechanisms involved in the homeostasis of glucose metabolism at rest and when stressed. New disorders causing hypoglycaemia are described using the classification based upon aetiologies, which was used in Bonham's original paper. The development and use of guidelines and pre-assembled packs for investigating hypoglycaemia is also discussed.
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Affiliation(s)
- Timothy F Lang
- Department of Clinical Biochemistry, University Hospital of North Durham, North Road, Durham DH1 5TW, UK.
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Genetic testing and counseling for hereditary neurological diseases in Mali. J Community Genet 2011; 2:33-42. [PMID: 22109722 DOI: 10.1007/s12687-011-0038-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Accepted: 01/21/2011] [Indexed: 10/18/2022] Open
Abstract
As genetic advances become incorporated into health care delivery, disparities between developing and developed countries may become greater. By addressing genetic health care needs and specific differences of developing countries, these disparities may be mitigated. We sought to describe the attitudes and knowledge of subjects with hereditary neurological diseases in Mali before and after receiving genetic testing and counseling for the first time. A questionnaire of attitudes and knowledge items was adapted and piloted for use in Mali. We found that the majority of subjects had positive attitudes toward genetic testing and counseling, both before and afterwards. Subjects responded to approximately half of the knowledge questions regarding hereditary transmission correctly before and after genetic testing and counseling. Neither overall attitudes nor knowledge scores changed significantly from baseline. Concerns about confidentiality were expressed by the majority of subjects. These findings indicate that, despite limited knowledge of patterns of inheritance, Malians understood the sensitive nature of this information and were favorable toward receiving genetic testing and counseling for diagnostic and prognostic purposes.
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