1. Treuman Katz Center for Pediatric Bioethics - 2008 Conference Expanding Newborn Screening 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

2. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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. While the factual information presented is referenced, any opinions stated are those of the presenter and not necessarily of the NIH or the DHHS.

3. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

4. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

5. Treuman Katz Center for Pediatric Bioethics - 2008 Conference PRESIDENT 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)

6. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

7. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

8. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

9. Treuman Katz Center for Pediatric Bioethics - 2008 Conference <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) 30-39 Disorders (12) 40-49 Disorders (15) 50+ Disorders (9) 20-29 Disorders (2) DC

10. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

11. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

12. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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.

13. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

14. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

15. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

16. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

17. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

18. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

19. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

20. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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 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

21. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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

22. Treuman Katz Center for Pediatric Bioethics - 2008 Conference 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