Expanding Newborn Screening

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Expanding Newborn Screening
Duane Alexander, M.D.
Director, Eunice Kennedy Shriver National
Institute of Child Health and Human Development
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DISCLAIMER

• While the factual information
• presented is referenced, any
• opinions stated are those of the presenter and
  not necessarily of
• the NIH or the DHHS.

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THE BEGINNING PKU

• Description by Foling 1934
• Proposals for dietary treatment by Woolf
• and others 1951
• Need for Rx to begin early (Bickel and
• Grueter 1960)
• Development and approval of Lofenalac 1958
• Robert Guthries screening test 1960

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IMPACT ON MENTAL RETARDATION

• Status before 1960
• Prevention of PKU sparked a fire
• Optimism could finally do something
• Shift of investigators to MR
• Shift of research from institutions to academic
  centers
• Find and treat other PKUs

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PRESIDENT KENNEDYS PROGRAM

• New Institute at NIH (NICHD) to fund MR research
• Presidents Committee on Mental Retardation
• Construction of MRRCs
• Establishment of UAFs
• Advertising Council Campaign advocating that
• the new PKU test should be a must for all
• babies everywhere
• (All in advance of data on effectiveness)

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CB/NICHD STUDY OF EFFICACY

• AAP report in 1965 noted lack of data on
  efficacy, said
• a collaborative study to evaluate management of
  this disease would be valuable.
• Also pointed out (without citation) that
  initially
• some infants were harmed by excessive or
  unnecessary treatment
• 1967 Launched U.S. Collaborative Study of
  Children
• treated for PKU (224 Children)
• Diet initiated early led to normal growth, levels
  of IQ comparable to sibs without PKU, should be
• maintained throughout childhood
• Best predictor age diet begun

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MANDATING SCREENING

• Following the lead of Massachusetts, New York,
  Louisiana, and Rhode Island, many states moved
  quickly to mandate newborn screening for PKU
• Prevalence 1 in 14,000 births
• Variants Non-PKU hyperphenylalaninemia
• False positives (95 of screen positives)
• False negatives (up to 10 missed)
• Efforts to improve

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OTHER PROBLEMS

• Dietary management
• Level of PA control
• How long to continue
• Maternal PKU
• NIH Consensus Conference
• Addition of other disorders
• National Research Council Report
• 1975
• Skip to today

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50 Disorders (9)
40-49 Disorders (15)
30-39 Disorders (12)
U.S. Newborn Screening Conditions Required June
1, 2006 (Conditions available as an option to
selected population are not counted)
20-29 Disorders (2)
10-19 Disorders (10)
lt10 Disorders (3)
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LESSONS LEARNED

• Proceed with caution to avoid harm, but proceed
  to take advantage of preventive potential
• If we apply the lessons learned when we broke new
  ground, we can implement expanded screening
  responsibly

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HOW TO PROCEED

• Make programs comparable across states
• Improve screening technology emphasizing
• DNA-based approaches
• Aggressively pursue development and testing
• of therapies for disorders currently lacking
• effective treatment
• Evaluate tests to minimize false positives and
  negatives

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HOW TO PROCEED (CONT)

• Have a confirmatory test system in place to
  operate quickly with clear parental counseling
• For treatable conditions, have a science-based
  service delivery and follow-up system in place
• Expand screening to include disorders that do not
  yet have proven preventive therapy available, and
  provide a registry of such patients (with
  parental approval) for possible future research
  participation.

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MAKE NBS PROGRAMS COMPARABLE ACROSS STATES

• The consequences of program variability
• Equity is an ethical imperative
• Current variability
• Sources of variability
• State legislation
• Payment system
• Costs of individual tests
• Variation in prevalence of conditions by state
• One corrective approach A single unified test
  system

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IMPROVE NBS TECHNOLOGY

• Current system different test for almost every
  disorder (same source -- blood spots but
  different tests)
• Impact of tandem mass spectroscopy (MS/MS)
• Potential DNA-based systems
• Screen for anything we have the gene for
• Genetic metabolic disorders with MR
• Immunodeficiencies
• Hemoglobinopathies, Coagulopathies
• Muscular dystrophies
• Cystic Fibrosis
• Hereditary deafness syndromes
• Congenital hypothyroidism separate
• NICHD solicitation

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DEVELOP NEW THERAPIES FOR DISORDERS WITHOUT
EFFECTIVE TREATMENT

• Part of justification for screening for these
• disorders
• Screening makes patients with rare disorders
• available for study of new treatments
  pre-symptomatically
• NICHD Solicitation
• Registry
• Consent

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EVALUATE TESTS TO MINIMIZE FALSE POSITIVES AND
NEGATIVES

• Balance in drawing cut-off lines
• Lab variability
• Concerns of costs and parental anxiety
• SACHDGDNC evaluating each new test before
  recommending addition
• Ongoing monitoring and standardization
• Regional Collaboratives/National Coordinating
  Center
• DNA-based system could help

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CONFIRMATORY TEST SYSTEM WITH PARENTAL COUNSELING

• Essential due to false positives/negatives in
  screening
• Included in SACHDGDNC criteria for adding new
  tests
• Regional Collaborative/National Coordinating
  Center
• Rapid, precise results confirmed by experts and
  conveyed by counselors to family and medical home

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TREATMENT INITIATION AND FOLLOW-UP MONITORING

• For treatable conditions and those lacking
  definitive therapy
• Regional collaboratives provide/refer
• Gather follow-up data on effectiveness under
  guidance of National Coordinating Center
• Each disorder, each treatment

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EXPAND SCREENING TO INCLUDE DISORDERS WITHOUT
DEFINITIVE TREATMENT

• Treating before symptoms develop is only way
• to intervene early enough in degenerative
• disorders
• Newborn screening only way to detect those
  without a previous affected sibling
• Requirements
• Consent to screen (parents prefer to alternative)
• Counseling
• Supportive treatment

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EXPAND SCREENING TO INCLUDE DISORDERS WITHOUT
DEFINITIVE TREATMENT

• Registry (maintained by RC/NCC or CDC)
• Parental consent
• Confidential
• List by disease
• Agree to be contacted when new therapy study is
  available
• Outcomes of studies maintained by registry

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THE LEGISLATIVE AND ETHICAL IMPERATIVE

• No ones DNA information should be used to
  discriminate against them in employment or
  insurance
• Unless we assure by national legislation that
  such discrimination will not happen, parents will
  be reluctant to have their newborns screened in a
  public program

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THE LEGISLATIVE AND ETHICAL IMPERATIVE (CONT)

• Proceeding with caution includes providing this
  protection as well as all the medical and
  laboratory procedures identified
• If we conscientiously apply what we have learned,
  provide the necessary funding support and
  continue to learn, newborn screening will take
  its full place among the most significant and
  effective public health measures of all time