Treuman Katz Center for Pediatric Bioethics - 2008 Conference Expanding Newborn Screening Duane Alexander, M.D. Director, Eunice Kennedy Shriver National

Treuman Katz Center for Pediatric Bioethics - 2008 Conference

Expanding Newborn Screening

Expanding Newborn Screening

Duane Alexander, M.D.Duane Alexander, M.D.

Director, Eunice Kennedy Shriver National Institute of Child Health

and Human Development

Director, Eunice Kennedy Shriver National Institute of Child Health

and Human Development


DISCLAIMERDISCLAIMER

While the factual information

presented is referenced, any

opinions stated are those of the presenter and not necessarily of

the NIH or the DHHS.

While the factual information

presented is referenced, any

opinions stated are those of the presenter and not necessarily of

the NIH or the DHHS.


THE BEGINNING: PKUTHE 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 Guthrie’s screening test 1960

• 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 Guthrie’s screening test 1960


IMPACT ON MENTAL RETARDATION

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

• 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


PRESIDENT KENNEDY’S PROGRAMPRESIDENT KENNEDY’S PROGRAM

• New Institute at NIH (NICHD) to fund MR research• President’s 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)

• New Institute at NIH (NICHD) to fund MR research• President’s 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)


CB/NICHD STUDY OF EFFICACYCB/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

• 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


MANDATING SCREENINGMANDATING 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

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


OTHER PROBLEMSOTHER 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

• 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


<10 Disorders (3)

10-19 Disorders (10)

U.S. Newborn Screening

Conditions Required – June 1, 2006

(Conditions available as an option to selected population are not counted)



50+ Disorders (9)

20-29 Disorders (2)

DC


LESSONS LEARNEDLESSONS 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

• 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


HOW TO PROCEEDHOW 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

• 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


HOW TO PROCEED (CONT’)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.

• 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.


MAKE NBS PROGRAMS COMPARABLE ACROSS STATES

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

• 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


IMPROVE NBS TECHNOLOGYIMPROVE 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

• 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


DEVELOP NEW THERAPIES FOR DISORDERS WITHOUT EFFECTIVE TREATMENT

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

• 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


EVALUATE TESTS TO MINIMIZE FALSE POSITIVES AND NEGATIVES

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

• 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


CONFIRMATORY TEST SYSTEM WITH PARENTAL COUNSELING

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

• 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


TREATMENT INITIATION AND FOLLOW-UP MONITORING

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

• 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


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

• 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




• 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

• 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


THE LEGISLATIVE AND ETHICAL IMPERATIVE

THE LEGISLATIVE AND ETHICAL IMPERATIVE

• No one’s 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

• No one’s 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


THE LEGISLATIVE AND ETHICAL IMPERATIVE (CONT’)

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

• 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

Documents

Treuman Katz Center for Pediatric Bioethics - 2008 Conference Expanding Newborn Screening Duane Alexander, M.D. Director, Eunice Kennedy Shriver National