Recent Expansion of Newborn Screening R. Rodney Howell, M. D. Professor of Pediatrics Miller School of Medicine University of Miami Founding Chair Secretary's Advisory Committee on Heritable Disorders In Newborns And Children November 16-18, 2011 Moscow, Russia US-Russia Scientific Forum Meeting

Newborn Screening Newborn screening developed worldwide from a keen interest and understanding of Inborn Errors of Metabolism- a term introduced by Garrod in 1908 Newborn Screening has focused historically on the identification of conditions that adversely affect the CNS Increasingly, conditions involving other areas, such as the immune and cardiac systems have been recommended for the newborn screening panel Newborn screening has been driven to a considerable extent by available technology, and increasingly by better understanding of conditions as well as by new diagnostic technologies and treatments.

Positive Urinary Ferric Chloride Test in PKU

Newborn Screening for Genetic Diseases in the United States  Routine newborn screening  Began in 1960s; now carried out in all 50 states  State sponsored public health programs; most successful  Initial testing targets  Phenylketonuria and similar conditions  Simple, reliable screening tests and proven treatment efficacy  Expansion of targets  State-by-state basis  Challenge  Extraordinary variation from state to state  Little systematic evaluation of the rationale for and/or the outcomes of screening 10

Newborn Screening for Genetic Diseases in the United States Over 4 million infants are screened each year Newborn screening is by far the most commonly performed testing for genetic diseases in the United States Over 4 million infants are screened each year Newborn screening is by far the most commonly performed testing for genetic diseases in the United States 11

Standardization of Newborn Screening in the United States  In 2001, Maternal and Child Health Bureau (HRSA) charged American College of Medical Genetics  To evaluate the scientific and medical information related to screening for specific conditions  To make recommendations based on this evidence  Expert group convened in December 2002  >70 physicians, scientists, consumers, state laboratorians, lawyers, ethicists, and others  Results reviewed by an independent newborn screening external review group  Newborn Screening: Toward a Uniform Screening Panel and System (report published in 2006) 12

Selection Criteria of Uniform Panel  Availability of treatment  Cost of treatment  Efficacy of treatment  Benefits of early intervention  Benefits of early identification  Acute management  Simplicity of therapy  Incidence of conditions  Identifiable at birth  Burden of disease  Mortality prevention  Availability of test  Test characteristics  Diagnostic confirmation 13

Uniform Screening Panel 29 Primary (Core) Conditions  All result in serious medical complications (e.g., developmental delay) and/or death if not recognized early  All children with these conditions benefit from early diagnosis and treatment 14

Uniform Screening Panel 29 Primary (Core) Conditions  20 conditions are disorders of amino acids, fatty acids, and organic acids  Detected by a sophisticated laboratory technique (tandem-mass spectroscopy)  3 are hemoglobinopathies (S/S, S/βThal, S/C)  6 other conditions  Biotinidase deficiency  Congentital adrenal hyperplasica  Cystic fibrosis  Congenital hypothyroidism  Galactosemia and disorders of hearing. 15

Uniform Screening Panel 25 Secondary Targets  Target compounds identified by the same methods as primary targets  Compounds at times present in abnormal amounts  Instances when these compounds are present in abnormal amounts are not completely understood  It is recommended that these secondary targets be reported  To improve the understanding of their significance  To accurately identify those situations on the primary panel (do not understand) 16

Burden of the Core Panel Conditions in the U.S. All conditions are rare Estimated annual number confirmed (most common) –Hearing loss: 5,064 –Primary congenital hypothyroidism: 2,156 –Sickle cell disease: 1,775 –Cystic fibrosis: 1,248 –Medium-chain acyl-CoA dehydrogenase deficiency: 239 A total of about 12,500 infants are diagnosed with the core conditions and treated each year in the US with the current newborn screening panel 17

Burden of the Core Panel Conditions in the US Untreated persons suffer enormous burdens –Persons with phenylketonuria have relatively normal lifespan Untreated: IQ that are under 20 Identified and Treated: Normal IQ Persons with medium-chain acyl-CoA dehydrogenase deficiency, the most common disorder of fatty acid oxidation, are at substantial risk for sudden death

Policies and Guidelines: Authorizing Legislation  Title XXVI of the Children’s Health Act of 2000 enacts 3 sections of the Public Health Service Act  Established the Advisory Committee on Heritable Disorders in Newborns and Children (1 st meeting in has since met 25 times through September, 2011)  Provides evidence-based recommendations to the Secretary of Health and Human Services  Broad charge but efforts have focused on newborn screening 19

Advisory Committee for Heritable Disorders in Newborns and Children  Focus on the ACMG Report  Unanimously accepted the Report  Made recommendation to the HHS Secretary to adopt and implement the Report  In time, the Secretary  Accepted the Committee recommendation  Designated this Uniform Screening Panel as a National Standard for newborn screening programs in the United States 20

Nomination Form for Inclusion of Conditions into the Recommended Screening Panel ftp://ftp.hrsa.gov/mchb/genetics/NominationForm.doc Condition Screening test Treatment References 21

 Rigorous process in place for review of nominations  9 nominations submitted and reviewed since 2007  6 conditions sent forward for external evidence review  4 have referred back to nominators for additional studies.  2 recommended for adding to the Recommended Uniform Panel  Severe Combined Immunodeficiency (SCID) and Critical Cyanotic Congenital Heart Disease  SCID has been accepted by Secretary Sebelius  CCCHD has also been accepted by Secretary Sebelius Nomination Process for Inclusion of Conditions into the Recommended Screening Panel 22

Major Challenges to Newborn Screening and Way Forward  Serious shortage of clinical experts in the area of inborn errors of metabolism which span most of the primary conditions detected by newborn screening  Example: The ACMG has identified funding for fellowships in biochemical genetics  Public health laboratories are stretched financially at a time when important new discoveries must be brought to the public  Example: detection of multiple disorders using single tests, automation, and other cost-saving technologies 23

Major Challenges to Newborn Screening and Way Forward  Lack of public education and understanding about the value newborn screening  Example: Genetic Alliance’s Newborn Screening Clearinghouse will provide a great opportunity for public education, among other functions  Retention and use of residual dried blood spots  Example: Kemper et al. Committee report: Considerations and recommendations for national guidance regarding the retention and use of residual dried blood spot specimens after newborn screening. (Genetics in Medicine 13:621, 2011)  Extensive professional and public input  Expected to provide direction for states in their own planning 24

Materials to Assist the Primary Care Provider with Immediate Information: The ACT Sheets and Diagnostic Algorithms Provide information to facilitate initial responses to screen positive –Cover all core and secondary target conditions in NBS panel derived from 31 primary markers Point of care education –Sent with newborn screening result from NBS labs Integrated into AAPs plans for Newborn Screening Clinical Report that updates the AAP Task Force report of 2000.

Newborn Screening Translational Research Network Coordinating Center A Network Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development

Statement of Work/ Objectives 1)Establish an organized network of State newborn screening programs and clinical centers - Collect information from state labs and registries that will provide information possible human subjects, validation sites as well as archival blood spots 2)Develop, implement and refine a national research informatics system for investigators and policy makers that dovetails with the established national clinics network -Informatics system to link researchers with potential subjects for trials -Liaison between researchers and registries, NBS programs and clinical centers -Actively link grantees with technology validation sites

Statement of Work/ Objectives 3)Establish and administer an efficient and reliable repository of residual dried blood spots comprised of those stored by State NBS programs and other resources. 4)Provide expertise and support to researchers related to regulatory requirements associated with informed consent, IRBs and state and local research policy associated with NBS. 5)Facilitate research on the development of new methods and technologies by maintaining close contact with the scientific and biomedical research communities.

Statement of Work/ Objectives 6)Facilitate research on screened and treated patients to define effectiveness of treatments and long-term outcomes through -Monitoring new approaches to treatment for screened disorders -Encourage and support outcome studies related to newborn screening 7)Provide statistical leadership and clinical trial design expertise for the individualized needs of researchers through the NBSTRN Coordinating Center 8)Facilitate the timely dissemination of research findings

Newborn Screening is a Great Bargain!  Some states require that their newborn screening programs bill for services and be wholly self-sufficient –Minnesota charges $106 for their panel (includes cost of hearing screening follow-up) $455 M/year –Based on these figures, newborn screening programs in the United States would cost $455 M/year (not including all diagnostic follow-up or treatment) –The General Accounting Office (2003) reported a cost of $120M/year for blood spot screening alone $24 B/year –For comparison, AHRQ reported that the top 6 selling drugs for hypercholesterolemia cost $24 B/year (2008) –We spend as much in <1 week on 6 drugs for hypercholesterolemia as for the entire newborn screening program in 1 year. 31