Publications by authors named "Fred Lorey"

46 Publications

A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders.

Int J Neonatal Screen 2020 Jun 30;6(2). Epub 2020 May 30.

Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

Newborn screening for one or more lysosomal disorders has been implemented in several US states, Japan and Taiwan by multiplexed enzyme assays using either tandem mass spectrometry or digital microfluidics. Another multiplex assay making use of immunocapture technology has also been proposed. To investigate the potential variability in performance of these analytical approaches, we implemented three high-throughput screening assays for the simultaneous screening for four lysosomal disorders: Fabry disease, Gaucher disease, mucopolysaccharidosis type I, and Pompe disease. These assays were tested in a prospective comparative effectiveness study using nearly 100,000 residual newborn dried blood spot specimens. In addition, 2nd tier enzyme assays and confirmatory molecular genetic testing were employed. Post-analytical interpretive tools were created using the software Collaborative Laboratory Integrated Reports (CLIR) to determine its ability to improve the performance of each assay vs. the traditional result interpretation based on analyte-specific reference ranges and cutoffs. This study showed that all three platforms have high sensitivity, and the application of CLIR tools markedly improves the performance of each platform while reducing the need for 2nd tier testing by 66% to 95%. Moreover, the addition of disease-specific biochemical 2nd tier tests ensures the lowest false positive rates and the highest positive predictive values for any platform.
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http://dx.doi.org/10.3390/ijns6020044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423013PMC
June 2020

Novel liver findings in ornithine transcarbamylase deficiency due to Xp11.4-p21.1 microdeletion.

Gene 2015 Feb 27;556(2):249-53. Epub 2014 Nov 27.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, UCLA Clinical Genomics Center, Los Angeles, California. Electronic address:

Ornithine transcarbamylase deficiency (OTCD, OMIM 311250), the most common urea cycle disorder, results in impaired synthesis of citrulline from carbamoyl phosphate and ornithine. Individuals have been identified with OTCD due to a contiguous gene deletion at Xp11.4-p21.1 and unique clinical features, described as the "extended OTCD phenotype". We present a male with neonatal-lethal OTCD due to a 1.87Mb microdeletion at Xp11.4-p21.1 (37126841-38998991 hg18). Autopsy revealed a novel histological finding of hepatocyte globular and granular inclusions. Such inclusions have not been described in OTCD or other metabolic disorders and are not an associated finding in neonatal liver failure due to other causes. The deleted region includes the gene SYTL5, potentially involved in RAB27A-dependent membrane trafficking in the liver and placenta. We propose that the contiguous gene deletion could contribute to the severity of the clinical presentation here and hypothesize that deletion of SYTL5 could contribute to the liver findings.
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http://dx.doi.org/10.1016/j.gene.2014.11.057DOI Listing
February 2015

Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.

JAMA 2014 Aug;312(7):729-38

Department of Pediatrics, University of California, San Francisco, San Francisco2UCSF Benioff Children's Hospital, San Francisco, California.

Importance: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births.

Objectives: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments.

Design: Epidemiological and retrospective observational study.

Setting: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test.

Main Outcomes And Measures: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked.

Results: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia.

Conclusions And Relevance: Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.
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http://dx.doi.org/10.1001/jama.2014.9132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492158PMC
August 2014

Identification of galactose-1-phosphate uridyl transferase gene common mutations in dried blood spots.

Clin Chim Acta 2014 Sep 25;436:298-302. Epub 2014 Jun 25.

No longer affiliated with Genetic Disease Screening Program, State of California.

Background: The California newborn screening program uses newborns' dried blood spots (DBS) to screen for more than 45 genetic disorders. Deficiency of galactose-1-phosphate uridyl transferase (GALT) is one of the metabolic genetic disorders screened using newborn DBS. During follow-up tests, common mutations of the GALT gene have been identified using whole blood samples. To avoid the stress of drawing an additional blood sample from newborns who are identified as presumptive positive for galactosemia, we developed a method to test common mutations in the GALT gene using blood spots.

Methods: This method involves DNA extraction from DBS, followed by polymerase chain reaction (PCR), and single nucleotide extension (SNE). SNE products were detected by capillary electrophoresis.

Results: In a double-blind study, GALT gene common mutations/variants: IVS2-2A>G, p.S135L, p.T138M, p.Q188R, p.L195P, p.Y209C, p.L218L, p.K285N, and p.N314D were detected in seventy-three DBS which had previously been screened and confirmed as positive in the California Newborn Screening Program. Mutations found using blood spots gave 100% concordance with mutations from previously genotyped whole blood samples.

Conclusions: This blood spot method decreases the genomic test turnaround time of GALT screened positive patients and potentially reduces emotional stress on families required to provide an additional blood draw.
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http://dx.doi.org/10.1016/j.cca.2014.06.011DOI Listing
September 2014

Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening.

Mol Genet Metab 2014 Apr 23;111(4):484-92. Epub 2014 Jan 23.

Genomics Section, Hawai'i Department of Health, Honolulu, HI, USA.

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid oxidation disorder with widely varying presentations that has presented a significant challenge to newborn screening (NBS). The Western States Regional Genetics Services Collaborative developed a workgroup to study infants with NBS positive for VLCADD. We performed retrospective analysis of newborns with elevated C14:1-acylcarnitine on NBS in California, Oregon, Washington, and Hawai'i including available confirmatory testing and clinical information. Overall, from 2,802,504 children screened, there were 242 cases screen-positive for VLCADD. There were 34 symptomatic true positive cases, 18 asymptomatic true positives, 112 false positives, 55 heterozygotes, 11 lost to follow-up, and 12 other disorders. One in 11,581 newborns had an abnormal NBS for suspected VLCADD. Comparison of analytes and analyte ratios from the NBS demonstrated statistically significant differences between true positive and false positive groups for C14:1, C14, C14:1/C2, and C14:1/C16. The positive predictive value for all true positive cases was 94%, 54%, and 23% when C14:1 was ≥2.0 μM, ≥1.0 μM, and ≥0.7 μM, respectively. Sequential post-analytical analysis could reduce the referral rate in 25.8% of cases. This study is the largest reported follow-up of infants with NBS screen-positive results for suspected VLCADD and demonstrates the necessity of developing comprehensive and consistent long-term follow-up NBS systems. Application of clinical information revealed differences between symptomatic and asymptomatic children with VLCADD. Comparison of NBS analytes and analyte ratios may be valuable in developing more effective diagnostic algorithms.
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http://dx.doi.org/10.1016/j.ymgme.2014.01.009DOI Listing
April 2014

Precursor-to-product ratios reflect biochemical phenotype in congenital adrenal hyperplasia.

Metabolomics 2014 Feb;10(1):123-131

Division of Endocrinology, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Bldg RB-1, Box 446, Torrance, CA 90502, USA.

Precursor-to-product ratios in steroid hormone metabolism may accurately reflect enzymatic activity and production of metabolites relative to their disappearance. The purpose of this study was to explore the use of direct precursor-to-product steroid ratios to discriminate between infants with congenital adrenal hyperplasia (CAH) due to 21- α -hydroxylase deficiency and infants with no disorder, thus characterizing the biochemical phenotype in CAH. Deidentified dried blood spot samples from confirmed CAH cases identified by newborn screen (CAH-positive, = 8) and from cases with no disorder (CAH-negative, = 10) were obtained from the California State Newborn Screening Program. Samples (∼6.25 mm circular spots) underwent methanol and water extraction (9:1 ratio). Deuterated steroids served as isotope internal standards. 17-α-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), androstenedione (A4) and cortisol (F) concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the 17-OHP/S, 17-OHP/A4, and S/F ratios were calculated. The mean 17-OHP and A4 concentrations in samples from CAH cases were significantly increased when compared to cases with no disorder ( = 0.003 for both). 17-OHP/S and 17-OHP/A4 ratios were also significantly elevated in CAH cases ( = 0.007 and < 0.001, respectively). In contrast, S and F concentrations and the S/F ratio were similar between the two groups. In CAH, the elevated 17-OHP/S ratio is a biomarker of diminished 21-α-hydroxylase activity, and the elevated 17-OHP/A4 ratio is a biomarker of adrenal androgen excess via increased 17,20-lyase activity. The similar S/F ratio indicates that the rate of production via 11-β-hydroxylase and disappearance of F is maintained in CAH.
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http://dx.doi.org/10.1007/s11306-013-0558-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904458PMC
February 2014

Analysis of cases of 3-methylcrotonyl CoA carboxylase deficiency (3-MCCD) in the California newborn screening program reported in the state database.

Mol Genet Metab 2013 Dec 17;110(4):477-83. Epub 2013 Sep 17.

Department of Pediatrics, University of California, Los Angeles, CA, USA.

Background And Methods: There are considerable uncertainty and debate regarding all aspects of newborn screen-positive cases of 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), including diagnostic criteria, clinical spectrum, morbidity, prognosis, and appropriate management. To address some of these questions, we queried data from the California Newborn Screening Program's Screening Information System (SIS) and available scanned laboratory reports on cases of 3-MCCD reported by 15 state contracted metabolic specialty care centers born between July 2005 and December 2010. We evaluated the completeness and utility of the database as a tool for clinical disease characterization.

Results: During the study period, 2,959,108 infants were screened and 71 infants were diagnosed with 3-MCCD for an overall incidence of 1:41,676. The availability of diagnostic biochemical laboratory data varied significantly from subject to subject. Using a new case classification based on biochemical severity, we found that 8 of the cases met our criteria for biochemically severe (category 1), 19 cases met our criteria for biochemically mild (category 2) that we suspect to possibly be hypomorphic variants or heterozygote carriers, and 44 cases could not be classified (category 3) as mild or severe based on the data available in SIS. Documentation of the treatment regimens also varied significantly with 49% receiving dietary modification and 44% receiving carnitine. 15% of cases were documented to have experienced at least one of the following symptoms: lethargy, vomiting, irritability, ketosis, poor feeding, or poor tone. The majority of the subjects were completely developmentally age appropriate at their last assessment.

Conclusions: The results suggest that a significant portion of the 3-MCCD "confirmed" cases have a mild biochemical phenotype. Moreover the majority of cases had insufficient data entered to allow for adequate clinical characterization of the cases. These findings raise the concern that a significant number of individuals receiving treatment for 3-MCCD may not have a clinically significant condition. Additionally, the utility of this data system could be improved if centers provided complete confirmatory test results and more specific documentation of clinical outcomes and health/developmental status. Further studies, including a clinical chart review, are necessary to validate the data and further characterize this cohort.
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http://dx.doi.org/10.1016/j.ymgme.2013.09.006DOI Listing
December 2013

Glycan-based biomarkers for mucopolysaccharidoses.

Mol Genet Metab 2014 Feb 29;111(2):73-83. Epub 2013 Jul 29.

Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093, USA. Electronic address:

The mucopolysaccharidoses (MPS) result from attenuation or loss of enzyme activities required for lysosomal degradation of the glycosaminoglycans, hyaluronan, heparan sulfate, chondroitin/dermatan sulfate, and keratan sulfate. This review provides a summary of glycan biomarkers that have been used to characterize animal models of MPS, for diagnosis of patients, and for monitoring therapy based on hematopoietic stem cell transplantation and enzyme replacement therapy. Recent advances have focused on the non-reducing terminus of the glycosaminoglycans that accumulate as biomarkers, using a combination of enzymatic digestion with bacterial enzymes followed by quantitative liquid chromatography/mass spectrometry. These new methods provide a simple, rapid diagnostic strategy that can be applied to samples of urine, blood, cerebrospinal fluid, cultured cells and dried blood spots from newborn infants. Analysis of the non-reducing end glycans provides a method for monitoring enzyme replacement and substrate reduction therapies and serves as a discovery tool for uncovering novel biomarkers and new forms of mucopolysaccharidoses.
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http://dx.doi.org/10.1016/j.ymgme.2013.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769472PMC
February 2014

Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years.

J Allergy Clin Immunol 2013 Jul;132(1):140-50

Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CA 94143-0519, USA.

Background: Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID).

Objective: We sought to report the first 2 years of TREC NBS in California.

Methods: Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked.

Results: Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry.

Conclusions: TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population.
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http://dx.doi.org/10.1016/j.jaci.2013.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759317PMC
July 2013

A pilot study using residual newborn dried blood spots to assess the potential role of cytomegalovirus and Toxoplasma gondii in the etiology of congenital hydrocephalus.

Birth Defects Res A Clin Mol Teratol 2013 Jul 28;97(7):431-6. Epub 2013 May 28.

Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA.

Background: Congenital hydrocephalus is a condition characterized by accumulation of cerebrospinal fluid in the ventricles of the brain. Prenatal infections are risk factors for some birth defects. This pilot study investigated whether residual dried blood spots (DBS) could be used to assess infections as risk factors for birth defects by examining the associations between prenatal infection with Toxoplasma gondii (T. gondii) or cytomegalovirus (CMV) with congenital hydrocephalus.

Methods: Case-infants with hydrocephalus (N=410) were identified among live-born infants using birth defects surveillance systems in California, North Carolina, and Texas. Control-infants without birth defects were randomly selected from the same geographic areas and time periods as case-infants (N=448). We tested residual DBS from case- and control-infants for T. gondii immunoglobulin M and CMV DNA. When possible, we calculated crude odds ratios (cORs) and confidence intervals (CIs).

Results: Evidence for prenatal T. gondii infection was more common among case-infants (1.2%) than control-infants (0%; p=0.11), and evidence for prenatal CMV infection was higher among case-infants (1.5%) than control-infants (0.7%; cOR: 2.3; 95% CI: 0.48, 13.99).

Conclusions: Prenatal infections with T. gondii and CMV occurred more often among infants with congenital hydrocephalus than control-infants, although differences were not statistically significant. This pilot study highlighted some challenges in using DBS to examine associations between certain infections and birth defects, particularly related to reduced sensitivity and specimen storage conditions. Further study with increased numbers of specimens and higher quality specimens should be considered to understand better the contribution of these infections to the occurrence of congenital hydrocephalus.
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http://dx.doi.org/10.1002/bdra.23138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526818PMC
July 2013

WITHDRAWN: Glycan-based biomarkers for mucopolysaccharidoses.

Dis Markers 2013 Feb 8. Epub 2013 Feb 8.

Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA, USA.

Ahead of Print article withdrawn by publisher. At request of the authors, this article will be published in the journal Cancer Biomarkers (ISSN 1574-0153).
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http://dx.doi.org/10.3233/DMA-130970DOI Listing
February 2013

Newborn screening for SCID identifies patients with ataxia telangiectasia.

J Clin Immunol 2013 Apr 20;33(3):540-9. Epub 2012 Dec 20.

Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143-0519, USA.

Purpose: Severe combined immunodeficiency (SCID) is characterized by failure of T lymphocyte development and absent or very low T cell receptor excision circles (TRECs), DNA byproducts of T cell maturation. Newborn screening for TRECs to identify SCID is now performed in several states using PCR of DNA from universally collected dried blood spots (DBS). In addition to infants with typical SCID, TREC screening identifies infants with T lymphocytopenia who appear healthy and in whom a SCID diagnosis cannot be confirmed. Deep sequencing was employed to find causes of T lymphocytopenia in such infants.

Methods: Whole exome sequencing and analysis were performed in infants and their parents. Upon finding deleterious mutations in the ataxia telangiectasia mutated (ATM) gene, we confirmed the diagnosis of ataxia telangiectasia (AT) in two infants and then tested archival newborn DBS of additional AT patients for TREC copy number.

Results: Exome sequencing and analysis led to 2 unsuspected gene diagnoses of AT. Of 13 older AT patients for whom newborn DBS had been stored, 7 samples tested positive for SCID under the criteria of California's newborn screening program. AT children with low neonatal TRECs had low CD4 T cell counts subsequently detected (R = 0.64).

Conclusions: T lymphocytopenia in newborns can be a feature of AT, as revealed by TREC screening and exome sequencing. Although there is no current cure for the progressive neurological impairment of AT, early detection permits avoidance of infectious complications, while providing information for families regarding reproductive recurrence risks and increased cancer risks in patients and carriers.
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http://dx.doi.org/10.1007/s10875-012-9846-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591536PMC
April 2013

Integrated and first trimester prenatal screening in California: program implementation and patient choice for follow-up services.

Prenat Diagn 2012 Nov 18;32(11):1077-83. Epub 2012 Aug 18.

California Department of Public Health, Genetic Disease Screening Program, Richmond, CA, USA.

Objectives: The California Prenatal Screening Program serves over 350,000 women annually. This study examines utilization rates for the various screening options and patient choices regarding follow-up services.

Methods: The study tracked patients with first trimester positive results for Down syndrome to examine patient decisions regarding follow-up services and/or additional screening and to identify determinants of patient decisions. For first trimester screen positive women who elected further screening, second trimester integrated screening results were analyzed. The Genetic Disease Screening Program Chromosome Registry was used to identify Down syndrome cases.

Results: Ethnicity, but not age, was a strong predictor of acceptance of prenatal diagnosis. Approximately 47% of first trimester screen positive women opted for further screening. Among these women, 46% percent received an integrated screen negative result. All but one confirmed Down syndrome case in this cohort were still screen positive.

Conclusions: Data from the California Prenatal Screening Program indicate that all of the major screening modalities continue to be utilized. The wide range of choices made by women with screen positive results demonstrate the importance of including multiple options within the Program. Providing integrated screening to first trimester Down syndrome screen positive women reduced the number of unnecessary invasive procedures.
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http://dx.doi.org/10.1002/pd.3961DOI Listing
November 2012

Enhanced interpretation of newborn screening results without analyte cutoff values.

Authors:
Gregg Marquardt Robert Currier David M S McHugh Dimitar Gavrilov Mark J Magera Dietrich Matern Devin Oglesbee Kimiyo Raymond Piero Rinaldo Emily H Smith Silvia Tortorelli Coleman T Turgeon Fred Lorey Bridget Wilcken Veronica Wiley Lawrence C Greed Barry Lewis François Boemer Roland Schoos Sandrine Marie Marie-Françoise Vincent Yuri Cleverthon Sica Mouseline Torquado Domingos Khalid Al-Thihli Graham Sinclair Osama Y Al-Dirbashi Pranesh Chakraborty Mark Dymerski Cory Porter Adrienne Manning Margretta R Seashore Jonessy Quesada Alejandra Reuben Petr Chrastina Petr Hornik Iman Atef Mandour Sahar Abdel Atty Sharaf Olaf Bodamer Bonifacio Dy Jasmin Torres Roberto Zori David Cheillan Christine Vianey-Saban David Ludvigson Adrya Stembridge Jim Bonham Melanie Downing Yannis Dotsikas Yannis L Loukas Vagelis Papakonstantinou Georgios S A Zacharioudakis Ákos Baráth Eszter Karg Leifur Franzson Jon J Jonsson Nancy N Breen Barbara G Lesko Stanton L Berberich Kimberley Turner Margherita Ruoppolo Emanuela Scolamiero Italo Antonozzi Claudia Carducci Ubaldo Caruso Michela Cassanello Giancarlo la Marca Elisabetta Pasquini Iole Maria Di Gangi Giuseppe Giordano Marta Camilot Francesca Teofoli Shawn M Manos Colleen K Peterson Stephanie K Mayfield Gibson Darrin W Sevier Soo-Youn Lee Hyung-Doo Park Issam Khneisser Phaidra Browning Fizza Gulamali-Majid Michael S Watson Roger B Eaton Inderneel Sahai Consuelo Ruiz Rosario Torres Mary A Seeterlin Eleanor L Stanley Amy Hietala Mark McCann Carlene Campbell Patrick V Hopkins Monique G de Sain-Van der Velden Bert Elvers Mark A Morrissey Sherlykutty Sunny Detlef Knoll Dianne Webster Dianne M Frazier Julie D McClure David E Sesser Sharon A Willis Hugo Rocha Laura Vilarinho Catharine John James Lim S Graham Caldwell Kathy Tomashitis Daisy E Castiñeiras Ramos Jose Angel Cocho de Juan Inmaculada Rueda Fernández Raquel Yahyaoui Macías José María Egea-Mellado Inmaculada González-Gallego Carmen Delgado Pecellin Maria Sierra García-Valdecasas Bermejo Yin-Hsiu Chien Wuh-Liang Hwu Thomas Childs Christine D McKeever Tijen Tanyalcin Mahera Abdulrahman Cecilia Queijo Aída Lemes Tim Davis William Hoffman Mei Baker Gary L Hoffman

Genet Med 2012 Jul 16;14(7):648-55. Epub 2012 Feb 16.

Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Purpose: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries.

Methods: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors.

Results: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events.

Conclusion: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.
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http://dx.doi.org/10.1038/gim.2012.2DOI Listing
July 2012

Birth prevalence of disorders detectable through newborn screening by race/ethnicity.

Genet Med 2012 Nov 5;14(11):937-45. Epub 2012 Jul 5.

Genetic Disease Screening Program, California Department of Public Health, Richmond, USA.

Purpose: The purpose of this study was to describe the birth prevalence of genetic disorders among different racial/ethnic groups through population-based newborn screening data.

Methods: Between 7 July 2005 and 6 July 2010 newborns in California were screened for selected metabolic, endocrine, hemoglobin, and cystic fibrosis disorders using a blood sample collected via heel stick. The race and ethnicity of each newborn was self-reported by the mother at the time of specimen collection.

Results: Of 2,282,138 newborns screened, the overall disorder detection rate was 1 in 500 births. The disorder with the highest prevalence among all groups was primary congenital hypothyroidism (1 in 1,706 births). Birth prevalence for specific disorders varied widely among different racial/ethnic groups.

Conclusion: The California newborn screening data offer a unique opportunity to explore the birth prevalence of many genetic disorders across a wide spectrum of racial/ethnicity classifications. The data demonstrate that racial/ethnic subgroups of the California newborn population have very different patterns of heritable disease expression. Determining the birth prevalence of these disorders in California is a first step to understanding the short- and long-term medical and treatment needs faced by affected communities, especially those groups that are impacted by more severe disorders.
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http://dx.doi.org/10.1038/gim.2012.76DOI Listing
November 2012

Increased incidence of profound biotinidase deficiency among Hispanic newborns in California.

Mol Genet Metab 2012 Aug 30;106(4):485-7. Epub 2012 May 30.

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

We report population findings from newborn screening for biotinidase deficiency in California, representing over 2,000,000 newborns. The incidence of profound deficiency was 1/73,629, higher than in other reported populations. Out of 28 patients with profound biotinidase deficiency, 19 were of Hispanic descent, suggesting an increased frequency among this group. Of the 28 patients, 23 underwent mutation analysis of the BTD gene, with one common mutation, 528G>T, found in 43.3% of Hispanic alleles tested.
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http://dx.doi.org/10.1016/j.ymgme.2012.05.017DOI Listing
August 2012

Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California.

Mol Genet Metab 2012 May 9;106(1):55-61. Epub 2012 Feb 9.

Department of Pediatrics, University of California at Los Angeles, Los Angeles, CA, USA.

Background: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation with highly variable biochemical, genetic, and clinical characteristics. SCADD has been associated with accumulation of butyryl-CoA byproducts, including butyrylcarnitine (C4), butyrylglycine, ethylmalonic acid (EMA), and methylsuccinic acid (MS) in body fluid and tissues. Differences in genotype frequencies have been shown between patients diagnosed clinically versus those diagnosed by newborn screening. Moreover, while patients diagnosed clinically have a variable clinical presentation including developmental delay, ketotic hypoglycemia, epilepsy and behavioral disorders, studies suggest patients diagnosed by newborn screening are largely asymptomatic. Scant information is published about the biochemical, genetic and clinical outcome of SCADD patients diagnosed by newborn screening.

Methods: We collected California newborn screening, follow-up biochemical levels, and ACADS mutation data from September, 2005 through April, 2010. We retrospectively reviewed available data on SCADD cases diagnosed by newborn screening for clinical outcomes.

Results: During the study period, 2,632,058 newborns were screened and 76 confirmed SCADD cases were identified. No correlations between initial C4 value and follow-up biochemical markers (C4, EMA or MS levels) were found in the 76 cases studied. We found significant correlation between urine EMA versus MS, and correlation between follow-up C4 versus urine EMA. Of 22 cases where ACADS gene sequencing was performed: 7 had two or more deleterious mutations; 8 were compound heterozygotes for a deleterious mutation and common variant; 7 were homozygous for the common variant c.625G>A; and 1 was heterozygous for c.625G>A. Significant increases in mean urine EMA and MS levels were noted in patients with two or more deleterious mutations versus mutation heterozygotes or common polymorphism homozygotes. Clinical outcome data was available in 31 patients with follow-up extending from 0.5 to 60 months. None developed epilepsy or behavioral disorders, and three patients had isolated speech delay. Hypoglycemia occurred in two patients, both in the neonatal period. The first patient had concomitant meconium aspiration; the other presented with central apnea, poor feeding, and hypotonia. The latter, a c.625G>A homozygote, has had persistent elevations in both short- and medium-chain acylcarnitines; diagnostic workup in this case is extensive and ongoing.

Conclusions: This study examines the largest series to date of SCADD patients identified by newborn screening. Our results suggest that confirmatory tests may be useful to differentiate patients with common variants from those with deleterious mutations. This study also provides evidence to suggest that, even when associated with deleterious mutations, SCADD diagnosed by newborn screening presents largely as a benign condition.
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http://dx.doi.org/10.1016/j.ymgme.2012.02.007DOI Listing
May 2012

An automated method on analysis of blood steroids using liquid chromatography tandem mass spectrometry: application to population screening for congenital adrenal hyperplasia in newborns.

Clin Chim Acta 2011 Nov 23;412(23-24):2076-84. Epub 2011 Jul 23.

California Department of Public Health, Genetic Disease Laboratory Branch, 850 Marina Bay Parkway, Richmond, CA 94804, USA.

Background: Newborn screening for congenital adrenal hyperplasia (CAH) is commonly accomplished by measurement of 17-α-hydroxyprogestrone (17-OHP) using enzyme immunoassay (EIA). EIA contributes a significant number of false positives. Therefore, second-tier steroid profile by liquid chromatography-tandem mass spectrometry (LC-MS/MS) is warranted.

Methods: Dried blood spots (DBS) were extracted with a mixture of methanol and water containing the deuterium labeled internal standards of d(8)-17-OHP, d(7)-androstenedione, and d(4)-cortisol. The final extracts were analyzed for 17-OHP, androstenedione and cortisol by LC-MS/MS in the multiple reaction monitoring (MRM) mode.

Results: Mean recoveries of the target analytes, 17-OHP, androstenedione and cortisol, were between 97 and 115% with an average intra- and inter-assay CVs ranging from 3.9-9.9% to 3.6-10.1%, respectively. The high efficiency of this method enabled us to test 11,598 specimens, identified as indeterminate by EIA in ~6 years; resulting in 809 presumptive positives reducing the false positives rate by 93%.

Conclusions: The three steroid profile provided better screening outcomes of CAH than 17-OHP concentration alone. Our sample preparation allowed high throughput using common laboratory chemicals. Using three internal standards significantly improved method precision and accuracy. The reduction in false positives significantly reduces anxiety for newborns and their families.
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http://dx.doi.org/10.1016/j.cca.2011.07.009DOI Listing
November 2011

The California Prenatal Screening Program: "options and choices" not "coercion and eugenics".

Genet Med 2011 Aug;13(8):711-3

Prenatal Screening Branch, California Department of Public Health, Richmond, California 94804, USA.

The California Prenatal Screening Program is designed to make prenatal screening available to the state's large and diverse population. The Program provides information to women which will allow them to make informed choices regarding prenatal screening and prenatal diagnosis. Since the Program's inception in 1986, women in California have had the option to participate in prenatal screening or to decline prenatal screening. The California Program offers prenatal diagnostic services to women whose screening tests indicate an increased risk for birth defects, including Down syndrome. Women can decline any or all of these follow-up services. Genetic counseling, diagnostic services, and the presentation of diagnostic results are performed by medical professionals (not State staff) who follow established guidelines for nondirective counseling. Program data clearly demonstrate that women in California have a wide range of options and make a wide range of choices regarding prenatal screening and prenatal diagnosis. California's comprehensive Prenatal Screening Program promotes optimal care for all women within all options and choices. The important and necessary communication among organizations and stakeholders involved in prenatal screening and diagnosis, and in related care for pregnant women and for people with Down syndrome, is not served by misrepresentation and inflammatory rhetoric.
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http://dx.doi.org/10.1097/GIM.0b013e3182272e25DOI Listing
August 2011

Detection rate of quadruple-marker screening determined by clinical follow-up and registry data in the statewide California program, July 2007 to February 2009.

Prenat Diagn 2011 Sep 27;31(9):901-6. Epub 2011 Jun 27.

Genetic Disease Screening Program, California Department of Public Health, Richmond, CA 94804, USA.

Objective: To evaluate the efficiency of California's quadruple-marker screening program and construct receiver-operating characteristic (ROC) curves.

Methods: This study included the screening records of 552 941 women during July 2007 to February 2009. The screen-positive women received clinical follow-up services at state-approved centers. We used the California Chromosome Defect Registry which includes clinical, laboratory, and demographic data from the prenatal diagnostic centers, cytogenetic laboratories, hospitals, and prenatal care providers. Risk calculations, screen-positive rates (SPRs), detection rates (DRs) for chromosomal abnormalities, and 95% confidence intervals (95% CIs) were determined. ROC curves comparing the quadruple-marker to triple-marker screening were constructed.

Results: The DR and SPR for trisomy 21 (N = 827) during the quadruple-marker time period were 75.7% (95% CI 72.8-78.6%) and 3.75% (95% CI 3.70-3.80%) compared with 77.4% (95% CI 75.0-79.7%) and 5.4% during the triple-marker phase. The DRs were 78.2% (95% CI 75.0-81.4%) with ultrasound dating and 66.9% (95% CI 59.7-74.0%) for last-menstrual-period-dated pregnancies. For trisomy 18, triploidy, and trisomy 13, the DRs were 84.3, 95.7, and 43.5%, respectively.

Conclusions: The DR for trisomy 21 in California's statewide quadruple-marker screening is very similar to the Program's previously reported DR using triple-marker screening. However, this was achieved at a lower SPR, demonstrating improved screening performance.
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http://dx.doi.org/10.1002/pd.2802DOI Listing
September 2011

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

Authors:
David M S McHugh Cynthia A Cameron Jose E Abdenur Mahera Abdulrahman Ona Adair Shahira Ahmed Al Nuaimi Henrik Åhlman Jennifer J Allen Italo Antonozzi Shaina Archer Sylvia Au Christiane Auray-Blais Mei Baker Fiona Bamforth Kinga Beckmann Gessi Bentz Pino Stanton L Berberich Robert Binard François Boemer Jim Bonham Nancy N Breen Sandra C Bryant Michele Caggana S Graham Caldwell Marta Camilot Carlene Campbell Claudia Carducci Sandra C Bryant Michele Caggana S Graham Caldwell Marta Camilot Carlene Campbell Claudia Carducci Rohit Cariappa Clover Carlisle Ubaldo Caruso Michela Cassanello Ane Miren Castilla Daisy E Castiñeiras Ramos Pranesh Chakraborty Ram Chandrasekar Alfredo Chardon Ramos David Cheillan Yin-Hsiu Chien Thomas A Childs Petr Chrastina Yuri Cleverthon Sica Jose Angel Cocho de Juan Maria Elena Colandre Veronica Cornejo Espinoza Gaetano Corso Robert Currier Denis Cyr Noemi Czuczy Oceania D'Apolito Tim Davis Monique G de Sain-Van der Velden Carmen Delgado Pecellin Iole Maria Di Gangi Cristina Maria Di Stefano Yannis Dotsikas Melanie Downing Stephen M Downs Bonifacio Dy Mark Dymerski Inmaculada Rueda Bert Elvers Roger Eaton Barbara M Eckerd Fatma El Mougy Sarah Eroh Mercedes Espada Catherine Evans Sandy Fawbush Kristel F Fijolek Lawrence Fisher Leifur Franzson Dianne M Frazier Luciana R C Garcia Maria Sierra García-Valdecasas Bermejo Dimitar Gavrilov Rosemarie Gerace Giuseppe Giordano Yolanda González Irazabal Lawrence C Greed Robert Grier Elyse Grycki Xuefan Gu Fizza Gulamali-Majid Arthur F Hagar Lianshu Han W Harry Hannon Christa Haslip Fayza Abdelhamid Hassan Miao He Amy Hietala Leslie Himstedt Gary L Hoffman William Hoffman Philis Hoggatt Patrick V Hopkins David M Hougaard Kerie Hughes Patricia R Hunt Wuh-Liang Hwu June Hynes Isabel Ibarra-González Cindy A Ingham Maria Ivanova Ward B Jacox Catharine John John P Johnson Jón J Jónsson Eszter Karg David Kasper Brenda Klopper Dimitris Katakouzinos Issam Khneisser Detlef Knoll Hirinori Kobayashi Ronald Koneski Viktor Kozich Rasoul Kouapei Dirk Kohlmueller Ivo Kremensky Giancarlo la Marca Marcia Lavochkin Soo-Youn Lee Denis C Lehotay Aida Lemes Joyce Lepage Barbara Lesko Barry Lewis Carol Lim Sharon Linard Martin Lindner Michele A Lloyd-Puryear Fred Lorey Yannis L Loukas Julie Luedtke Neil Maffitt J Fergall Magee Adrienne Manning Shawn Manos Sandrine Marie Sônia Marchezi Hadachi Gregg Marquardt Stephen J Martin Dietrich Matern Stephanie K Mayfield Gibson Philip Mayne Tonya D McCallister Mark McCann Julie McClure James J McGill Christine D McKeever Barbara McNeilly Mark A Morrissey Paraskevi Moutsatsou Eleanor A Mulcahy Dimitris Nikoloudis Bent Norgaard-Pedersen Devin Oglesbee Mariusz Oltarzewski Daniela Ombrone Jelili Ojodu Vagelis Papakonstantinou Sherly Pardo Reoyo Hyung-Doo Park Marzia Pasquali Elisabetta Pasquini Pallavi Patel Kenneth A Pass Colleen Peterson Rolf D Pettersen James J Pitt Sherry Poh Arnold Pollak Cory Porter Philip A Poston Ricky W Price Cecilia Queijo Jonessy Quesada Edward Randell Enzo Ranieri Kimiyo Raymond John E Reddic Alejandra Reuben Charla Ricciardi Piero Rinaldo Jeff D Rivera Alicia Roberts Hugo Rocha Geraldine Roche Cheryl Rochman Greenberg José María Egea Mellado María Jesús Juan-Fita Consuelo Ruiz Margherita Ruoppolo S Lane Rutledge Euijung Ryu Christine Saban Inderneel Sahai Maria Isabel Salazar García-Blanco Pedro Santiago-Borrero Andrea Schenone Roland Schoos Barb Schweitzer Patricia Scott Margretta R Seashore Mary A Seeterlin David E Sesser Darrin W Sevier Scott M Shone Graham Sinclair Victor A Skrinska Eleanor L Stanley Erin T Strovel April L Studinski Jones Sherlykutty Sunny Zoltan Takats Tijen Tanyalcin Francesca Teofoli J Robert Thompson Kathy Tomashitis Mouseline Torquado Domingos Jasmin Torres Rosario Torres Silvia Tortorelli Sandor Turi Kimberley Turner Nick Tzanakos Alf G Valiente Hillary Vallance Marcela Vela-Amieva Laura Vilarinho Ulrika von Döbeln Marie-Francoise Vincent B Chris Vorster Michael S Watson Dianne Webster Sheila Weiss Bridget Wilcken Veronica Wiley Sharon K Williams Sharon A Willis Michael Woontner Katherine Wright Raquel Yahyaoui Seiji Yamaguchi Melissa Yssel Wendy M Zakowicz

Genet Med 2011 Mar;13(3):230-54

Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

Purpose: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort.

Methods: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25–30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration.

Results: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341).

Conclusion: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders.
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http://dx.doi.org/10.1097/GIM.0b013e31820d5e67DOI Listing
March 2011

Improved tandem mass spectrometry (MS/MS) derivatized method for the detection of tyrosinemia type I, amino acids and acylcarnitine disorders using a single extraction process.

Clin Chim Acta 2011 May 7;412(11-12):873-9. Epub 2011 Jan 7.

California Department of Public Health, Genetic Disease Laboratory Branch, 850 Marina Bay Pkwy, Richmond, CA 94804, United States.

Background: Succinylacetone (SUAC), a specific marker for tyrosinemia type I (Tyr I) cannot be detected by the routine LC-MS/MS screening of amino acids (AA) and acylcarnitines (AC) in newborns. The current derivatized methods require double extraction of newborn dried blood spots (DBS); one for AA and AC and the second for SUAC from the blood spot left after the first extraction. We have developed a method in which AA, AC and SUAC are extracted in a single extraction resulting in significant reduction in labor and assay time.

Methods: The 3.2 mm DBS were extracted by incubating at 45 °C for 45 min with 100 μl of acetonitrile (ACN)-water-formic acid mixture containing hydrazine and stable-isotope labeled internal standards of AA, AC and SUAC. The extract was derivatized with n-butanolic-HCl and analyzed by LC-MS/MS.

Results: The average inter-assay CVs for, AA, AC and SUAC were 10.1, 10.8 and 7.1% respectively. The extraction of analytes with ACN-water mixture showed no significant difference in their recovery compared to commonly used solvent MeOH. The concentration of hydrazine had considerable impact on SUAC extraction.

Conclusion: We developed a new MS/MS derivatized method to detect AA/AC/SUAC in a single extraction process for screening Tyr I along with disorders of AA and AC.
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http://dx.doi.org/10.1016/j.cca.2010.12.028DOI Listing
May 2011

The context and approach for the California newborn screening short- and long-term follow-up data system: preliminary findings.

Genet Med 2010 Dec;12(12 Suppl):S242-50

Genetic Disease Screening Program, California Department of Public Health, Richmond, California 94804, USA.

Purpose: State newborn screening programs are designed to prevent morbidity and mortality from hereditary disorders through early detection and ongoing disease management. These programs have traditionally focused on short-term follow-up. However, capturing data on the long-term follow-up process is emerging as a new priority. Long-term follow-up data can be used to assess the accessibility, continuity, and quality of care provided to these children. The California Newborn Screening Program uses a Web-based data collection system for short- and long-term follow-up. This article provides a description of the follow-up data collection system in addition to preliminary findings to demonstrate the efficacy of the California data collection approach.

Methods: A preliminary analysis of short-term follow-up data collected from July 7, 2005, through April 30, 2009, and a preliminary analysis of long-term follow-up data collected from July 1, 2007, through April 30, 2009.

Results: A majority of children are able to access ongoing care through age 5 years. The majority also have positive health outcomes at each year of follow-up.

Conclusion: California's short- and long-term data collection system can serve as a model for other states interested in implementing a comprehensive Newborn Screening Program follow-up data system.
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http://dx.doi.org/10.1097/GIM.0b013e3181fe5d66DOI Listing
December 2010

Effect of specimen storage conditions on newborn dried blood spots used to assess Toxoplasma gondii immunoglobulin M (IgM).

Clin Chim Acta 2011 Feb 27;412(5-6):455-9. Epub 2010 Nov 27.

Centers for Disease Control and Prevention, Atlanta, GA, United States.

Background: Newborn screening programs store-under varying conditions-residual dried blood spots (DBS). Residual DBS were used to investigate the contribution of congenital infection with Toxoplasma gondii to the etiology of hydrocephalus and as a key step, we assessed the effect of storage conditions on the stability of newborn screening biomarkers.

Methods: Infants with hydrocephalus (410 cases) were identified using population-based birth defects surveillance systems in California, North Carolina, and Texas. Infants without birth defects (448 controls) were randomly selected from the same geographic areas and time periods. California stores DBS with controlled temperature, while North Carolina and Texas store DBS under ambient conditions. After removal of personal identifiers, DBS were tested for Toxo-specific immunoglobulin-M (Toxo-IgM). Because of poor elution of DBS stored in ambient conditions, additional biomarkers were tested on a specimen subset.

Results: Among 858 DBS tested, Toxo-IgM was found in 3 cases and no controls from California (N=515) and in no specimens from North Carolina or Texas (N=343). Among the 98 specimens tested for selected biomarkers, statistically significant differences were found for California vs. combined North Carolina and Texas DBS (thyroid stimulating hormone, phenylalanine, methionine, leucine and citrulline p<0.0001; tyrosine and valine p<0.001).

Conclusions: Storage conditions for residual DBS had an effect on the ability to extract, recover, and accurately measure Toxo-IgM and other biomarkers from the filter paper matrix.
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http://dx.doi.org/10.1016/j.cca.2010.11.028DOI Listing
February 2011

Ancillary benefits of prenatal maternal serum screening achieved in the California program.

Prenat Diagn 2010 Oct;30(10):981-7

Genetic Disease Screening Program, California Department of Public Health, 850 Marina Bay Parkway, Richmond, CA 94804, USA.

Objective: To evaluate the extent of fetal structural abnormalities, other than neural tube and abdominal wall defects (AWDs), identified by California's Prenatal Screening Program.

Methods: The Quad Marker Prenatal Screening records of 516,172 women were examined for screening interpretation and the diagnosis of structural abnormalities detected via follow-up. Women who were screen-positive for trisomy 21, trisomy 18, neural tube defects (NTDs) or Smith-Lemli-Opitz syndrome (SLOS) received follow-up services at state-approved Prenatal Diagnosis Centers (PDCs). Detailed reports of services and diagnostic information were linked in a database to the original screening results.

Results: A total of 26 323 women received follow-up ultrasound services at the PDCs in the study time period. Of these women, 1085 (4.1%) were identified as having fetuses with significant structural abnormalities, other than NTDs (n = 207) or AWDs (n = 254). In addition to the structural abnormalities, 225 cases of fetal demise, 4 molar pregnancies, 15 cases of twin-to-twin transfusion, and 92 cases with placental abnormalities were identified.

Conclusion: While Prenatal Screening Programs do not explicitly screen for structural abnormalities other than NTDs and AWDs, clearly many other structural abnormalities may be associated with a screen-positive status. Thus, the detection of these additional structural defects can be considered an ancillary program benefit.
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http://dx.doi.org/10.1002/pd.2601DOI Listing
October 2010

Trends in incidence rates of congenital hypothyroidism related to select demographic factors: data from the United States, California, Massachusetts, New York, and Texas.

Pediatrics 2010 May;125 Suppl 2:S37-47

Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.

Primary congenital hypothyroidism (CH) is a common and preventable cause of intellectual disability. The incidence rate of CH has been reported to be increasing in the United States, but the factors behind the observed rate increase are not known. We summarize here the data presented at a workshop on CH, at which factors potentially related to the CH-incidence-rate increase (namely, race, ethnicity, sex, and birth outcomes) were evaluated. Data sources for the analyses included a national data set of newborn-screening results and state-specific data from newborn-screening programs in California, Massachusetts, New York, and Texas. The incidence rate of CH increased in the United States by 3% per year; however, an increase did not occur in all states, at a constant rate, or even at the same rate. Analysis of US data (1991-2000) showed a CH-incidence-rate increase only among white newborns. More recently, in California (2000-2007), the rate was constant in non-Hispanic newborns, but it increased among Hispanic newborns. In the national data, the CH-incidence rate increased similarly among boys and girls, whereas in Texas (1992-2006), the rate among boys increased significantly more than among girls and varied according to race and ethnicity. In Massachusetts (1995-2007), low birth weight newborns or newborns who had a delayed rise in thyrotropin concentration accounted for the majority of the recent rate increase. Race, ethnicity, sex, and pregnancy outcomes have affected the observed increasing incidence rate of CH, although there have been some inconsistencies and regional differences. The association with preterm birth or low birth weight could reflect the misclassification of some cases of transient hypothyroxinemia as true CH. Future studies of risk factors should focus on correct initial identification and reporting of demographic characteristics and pregnancy outcomes for cases of CH. In addition, long-term follow-up data of presumed cases of CH should be ascertained to differentiate true cases of CH from cases of transient hypothyroidism.
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http://dx.doi.org/10.1542/peds.2009-1975DDOI Listing
May 2010

Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and other remethylation disorders with tandem mass spectrometry.

J Pediatr 2010 Aug 14;157(2):271-5. Epub 2010 Apr 14.

Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN 55905, USA.

Objective: To validate a 2-tier approach for newborn screening (NBS) of remethylation defects.

Study Design: The original NBS dried blood spots of 5 patients with a proven diagnosis of a remethylation disorder and 1 patient with biochemical evidence of such disorder were analyzed retrospectively to determine disease ranges for methionine (Met; 4.7-8.1 micromol/L; 1 percentile of healthy population, 11.1 micromol/L), the methionine/phenylalanine ratio (Met/Phe; 0.09-0.16; 1 percentile of healthy population, 0.22), and total homocysteine (tHcy; 42-157 micromol/L; 99 percentile of normal population, 14.7 micromol/L). These preliminary disease ranges showed a sufficient degree of segregation from healthy population data, allowing the selection of cutoff values. A simple algorithm was then developed to reflex cases to a second-tier testing for tHcy, which has been applied prospectively for 14 months.

Results: A total of 86 333 NBS samples were tested between January 2007 and March 2008, and 233 of them (0.27%) met the criteria for second-tier testing of tHcy. All cases revealed concentrations of tHcy <15 micromol/L and were considered unaffected. No false-negative results have been reported with a state-wide system based on 2 combined metabolic clinics and laboratories that cover the entire Minnesota population and border areas of neighboring states.

Conclusions: Pending more conclusive evidence from the prospective identification of additional true-positive cases, NBS for remethylation disorders appears to be feasible with existing methodologies, with only a marginal increase of the laboratory workload.
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http://dx.doi.org/10.1016/j.jpeds.2010.02.027DOI Listing
August 2010

Asymptomatic maternal combined homocystinuria and methylmalonic aciduria (cblC) detected through low carnitine levels on newborn screening.

J Pediatr 2009 Dec;155(6):924-7

Division of Medical Genetics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

A symptom-free woman gave birth to a girl with a low carnitine level on newborn screening. The baby was unaffected, but the mother had biochemical abnormalities and mutations characteristic of the cblC defect of vitamin B(12) metabolism (late-onset form). This patient with cblC was detected through her infant's newborn screening.
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http://dx.doi.org/10.1016/j.jpeds.2009.06.046DOI Listing
December 2009

Triple-Marker Prenatal Screening Program for Chromosomal Defects.

Obstet Gynecol 2009 Oct;114(4):929

Genetic Disease Screening Program, California Department of Public Health, Richmond, California (Kazerouni, Currier, Lorey, Roberson).

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http://dx.doi.org/10.1097/01.AOG.0b013e3181ba09e6DOI Listing
October 2009

Triple-marker prenatal screening program for chromosomal defects.

Obstet Gynecol 2009 Jul;114(1):50-58

From the Genetic Disease Screening Program, California Department of Public Health, Richmond, California.

Objective: To examine screening performance of California's triple-marker screening program, using data from a statewide registry for chromosomal defects.

Methods: This study included 752,686 women who received a screening risk and had an expected date of delivery between July 2005 and the end of June 2007. Follow-up diagnostic services for screen-positive women were performed at state-approved centers. Data on diagnostic outcomes from these visits were entered into the California Chromosomal Defect Registry (CCDR). Other CCDR sources include mandatory reporting by all cytogenetic laboratories and hospitals and outcome data forms submitted by prenatal care providers.

Results: The observed detection rate for Down syndrome (N=1,217) was 77.4%. It varied significantly by gestational dating method and maternal age. The rates for women aged younger than 35 years and 35 years and older were 62.4% and 94.0%, respectively. The detection rates were 81.3% for ultrasound-dated pregnancies and 67.5% for last menstrual period-dated pregnancies. For Turner syndrome, trisomy 18, triploidy, and trisomy 13, the detection rates were 79.4%, 82.5%, 98.1%, and 36.0%, respectively. The positive rate for Down syndrome was 5.4%. Of women with a Down syndrome fetus who were screen positive, only 49.5% opted for amniocentesis. Of women who obtained results from amniocentesis indicating a Down syndrome fetus, 61.4% had an elective termination, 26.2% had a live birth, 4.5% had a death or miscarriage, and 7.9% had an unknown outcome.

Conclusion: The observed performance of this large triple-marker screening program exceeds generally predicted detection rates for Down syndrome. This study methodology will be used to measure the performance of subsequent screening enhancements.

Level Of Evidence: III.
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http://dx.doi.org/10.1097/AOG.0b013e3181a9479eDOI Listing
July 2009