LPDR Projects

Severe Combined Immunodeficiencies

Principal Investigator: Michele Caggana, ScD

Institution: New York State, Department of Health-Wadsworth Center

Project Start Date: August 2010

Project End Date: June 2011

“National SCID Pilot Study”

The “National SCID Pilot Study,” funded as an extension of the “Novel Technologies” contract awarded to New York, had the goal of providing comprehensive newborn screening for severe combined immunodeficiency for as many newborns as possible. California, Louisiana (Wisconsin Newborn Screening Program), Puerto Rico (New England Newborn Screening Program), and New York participated, based on population demographics and/or size.  Deliverables of this contract included establishment of the T-cell receptor excision circle assay into routine, high-volume newborn screening protocols, creation of laboratory and clinical follow-up algorithms, mechanisms for reporting, and protocols for treatment. The collaborative established a portal in the Region 4 Stork Collaborative website for deposition of SCID cases.  Lastly, the group created a guidance table that collates assay variables, equipment, and other pertinent information for other Programs. The Newborn Screening Translational Research Network provided assistance with meetings, phone calls, and organization of all interested parties. In total 654,053 babies were screened, and 307 were referred. A total of 12 babies were confirmed with SCID (1/54,504), 3 babies were confirmed with a SCID variant, and 38 babies were confirmed with an immunodeficiency related to another condition. No babies were diagnosed with SCID who were not detected via screening.  The National SCID Pilot Study assessed screening technologies for SCID and established confirmatory tests and definitions for presumed positive cases. A new module of the laboratory performance tool was developed to support the analytical and clinical validation of SCID screening.  The NBSTRN SCID screening laboratory performance tool was designed to capture data related to the analytical and clinical validation of the TREC assay for a pilot of SCID newborn screening, and it has proven useful as SCID joins the panel of screened conditions in many states. This is a useful model for future investigations of new technologies and conditions.

Statement of Work for the National SCID Pilot Study

April 2014 SCID ImplementationStatus -  Map of the USA

List of Appendices:

  1. New York Standard Operating Procedure for TREC Analysis
  2. New York SCID Validation
  3. LA/WI Validation and Standard Operating Procedure for Receipt for Specimens and Transmission of Results
  4. PR/MA Validation and Standard Operating Procedure for Receipt for Specimens and Transmission of Results
  5. Assay Elements Spreadsheet
  6. NY Laboratory Algorithm
  7. CA Laboratory Algorithm
  8. NY Clinical Algorithm
  9. CA Clinical Algorithm and Special Instructions for Repeat Testing
  10. LA Information for Providers
  11. CA Educational Materials for Families and Providers:
  12. NY Educational Materials for Families and Providers

Novel Technologies in NBS Report

Lysosomal Storage Disorders Collaborative

Principal Investigator: Melissa Wasserstein, MD 

Institution: Mount Sinai School of Medicine

Project Start Date: September 4, 2012

Project End Date: May 31, 2017

“LSDs: A Pilot NBS and Examination of the Associated Ethical Legal and Social Issues”

Newborn screening for several LSDs (Fabry, Gaucher, Niemann Pick Types A and B, and Pompe) has been proposed in several states. Each of these diseases has a broad phenotypic spectrum ranging from severe infantile-onset disease to adult-onset, milder phenotypes. Thus, newborn screening for these disorders presents a unique set of complex issues that require investigation prior to the initiation of mass newborn screening. These issues include determining the clinical and diagnostic accuracy of the screening assay, investigating how to correctly predict phenotype in asymptomatic newborns, and developing algorithms to assist with clinical decision-making about if and when to initiate therapy. In addition, there are novel ethical, legal, and social issues associated with testing infants for potentially later-onset disorders. This proposal will explore these issues by implementing a pilot newborn screen in approximately 80,000 infants born in high birth rate, ethnically diverse New York City hospitals in order to evaluate the analytic and clinical validity of the screening test and to determine disease incidence in an ethnically diverse population. Screening data will be shared with the Newborn Screening Translational Research Network (NBSTRN). Natural history data generated from this research and from existing disease-specific clinical databases will also be shared with the NBSTRN, with the goal of developing models to predict age of onset of disease over the lifespan in order to optimize treatment and avoid premature use of costly therapies. Prospective clinical, laboratory, and radiographic data will be collected and analyzed in order to develop evidence-based algorithms for the diagnosis and treatment of these rare disorders. In addition, the unique ethical, legal, and psychosocial issues that are associated with screening for these disorders will be explored.

Inborn Errors of Metabolism

Principal Investigators: Cynthia Cameron, PhD and Susan Berry, MD

Institution(s): Michigan Public Health Institute and University of Minnesota

Project Start Date: April 15, 2011

Project End Date:  February 29, 2016

“Collaborative Defining the Natural History of Inborn Errors of Metabolism”

To verify the effectiveness of early identification, intervention, and treatment, longitudinal assessment of outcomes is essential. A better understanding of the natural histories of rare metabolic disorders and the effectiveness of current treatments is necessary to provide optimum care and promote the best possible outcomes for children with these conditions. The Inborn Errors of Metabolism Collaborative (IBEMC), consisting of 13 clinics from 10 states, will collect longitudinal data that capture the clinical progress of persons affected with conditions identified by newborn screening, focusing on inborn errors of metabolism. Data will be used to better define the natural histories and understand the effect of treatment interventions. The database will allow for: 1. Investigation of the relationship among NBS values, genotype, and early manifestations as well as complications of inborn errors of metabolism; 2. Evaluation of the impact of early identification and intervention on metabolic conditions; 3. Informed decision making about optimal public health investment in NBS; 4. Clarification of the previously undefined natural history of very rare metabolic conditions; and 5. Identification of current nutritional and therapeutic interventions for children with metabolic conditions and evaluation of their effectiveness. The IBEMC will build on the work of the HRSA-funded Region 4 Genetics Collaborative and be developed in collaboration with other national efforts, including the Newborn Screening Translational Research Network. As a sufficient number of cases are entered for the rarer disorders, research will provide evidence as to the efficacy of early diagnosis and treatment.

For more information visit: www.ibem-is.org or email info@ibem-is.org 

Spinal Muscular Atrophy

Principal Investigator: Kathryn J. Swoboda, MD, FACMG

Institution: Motor Disorders Research Program Department of Neurology - University of Utah

Project Start Date: April 20, 2011

Project End Date: March 31, 2016

“Newborn screening for identification and prospective follow-up of infants with SMA”

With an incidence of 1 in 10,000 births, Spinal Muscular Atrophy (SMA) is one of the most common lethal genetic diseases. In the past decade, the development and increasingly widespread implementation of standard of care protocols and proactive nutritional as well as respiratory support has dramatically improved survival in babies with the severe infantile variant, SMA type I, which accounts for more than 50% of affected children. However, improved survival has not resulted in improved motor outcomes in those identified following the onset of symptoms, largely due to rapid progression during the acute phase, followed by a plateau phase characterized by up to several years of functional stability.  

This study is implementing a multi-state, multi-region newborn screening (NBS) pilot study to assess the feasibility of a DNA-based assay for homozygous SMN1 deletion to detect infants at risk for the development of SMA, in the NBS laboratory setting. In doing so, the research team hypothesize: 1) that the incidence of affected newborns will parallel predictions from early pilot data, and 2) that identification of infants at risk for SMA via NBS will improve outcomes, including morbidity, mortality, and motor function, as compared to a natural history cohort provided the same proactive nutritional, respiratory, and clinical care protocols via a subspecialty-based medical home. In the current application, the investigators will also explore ethical, regulatory, and policy issues regarding the use of NBS to pilot screen for SMA to identify the most optimal consent model. To attempt to improve outcomes in the pre-symptomatic population identified with NBS, they will implement and assess the impact of a multidisciplinary approach to management on health outcomes of SMA infants identified via the proposed pilot. Screening 400,000 newborns, the investigators expect to identify at least 40 infants at risk for SMA.  The investigators worked with the NBSTRN staff to create standardized case report forms for SMA within the LPDR and plan to deposit diagnosed cases in the VRDBS.

For more information about this project please contact the PI at Swoboda@genetics.utah.edu.