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The Exciting, Emotional and often Misunderstood World of

The Exciting, Emotional and often Misunderstood World of. NEWBORN SCREENING. Bill Lefkowitz December-ish 2001. PKU (Phenylketonuria)

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The Exciting, Emotional and often Misunderstood World of

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  1. The Exciting, Emotional and often Misunderstood World of NEWBORN SCREENING Bill Lefkowitz December-ish 2001

  2. PKU (Phenylketonuria) Disorder of phenylalanine hydroxylation leading to accumulation of this amino acid. Patients with undiagnosed PKU have progressive developmental delay in the first year of life, severe mental retardation, seizures, autistic-like behavior and a peculiar odor. Test: Bacterial inhibition assay to measure blood phenylalanine Using a cut-off level of 4 mg/dL, miss 16% under 24 hours, 2% over 48 hours old Guthrie bacterial inhibition test: the prototype of metabolic screening tests relying on bacterial inhibition. Filter paper is saturated with heel-stick blood, allowed to dry, small disks are punched out for use in tests. Bacillus subtilis is spread uniformly on agar. Inhibitory amino acid analogs block specific metabolic pathways. Bacterial can grow only if exogenous amino acids competitively overcome the block. Can test in this manner for phenylalanine, leucine, methionine, galastosemia, histidine, and tyrosine. Antibiotics can also inhibit growth, however, causing false negatives. False positives (1-3% of cases) non-PKU hyperphenylalanemia (1/60,000) pterin defect with secondarily hyperphenylalanemia transient elevation, acute galatosemia False negatives incorrect age, s/p transfusion urine screening unreliable in infants GeneticsAutosomal recessive 1:10,000 to 1:25,000 in US 1:6,000 in Ireland, Scotland and among the Yemenite Jews Frequently seen with biopterin and dihydropteridine reductase deficiencies DNA mutation heterogenous PathologyMost commonly causes by a deficiency of phenylalanine hydroxylase leading to an accumulation of phenylalanine, which impairs the development of the central nervous system DiagnosisRarely diagnosed before 6 months and usually only after mental retardation is obvious Paler and fairer than siblings because melanin formation is competitively inhibited by high phenylalanine levels Progressive developmental delay in the first year of life, severe mental retardation, seizures, autistic-like behavior and a peculiar odor. Hyperactivity and eczema also common. TreatmentDietary restriction of phenylalanine is highly effective if begun before the infant is 4 weeks old. Diet requires protein restriction and avoidanace of aspartame.

  3. Introduction • Principles of Screening • Lessons from the History of Newborn Screening • Some specifics about Maryland NBS • The Other Controversies in Newborn Screening • Why the heck would anyone refuse newborn screening !?! • Summary and closing points with references

  4. Principles of Screening • What makes a test a screening test? • Diagnostic test used to establish diagnosis • Screening test used to distinguish those who PROBABLY have the disorder from those who probablyDON’T have the disorder • A “POSITIVE” screening test must be followed up by a definitive diagnostic test! • It’s not the test, it’s how you use it…

  5. Properties of a good (screening) test Cheap and quick Accurate and reproducible Noninvasive Has a good statistical profile How well the test result predicts the diagnosis Positive and Negative Predicitive Values How much the diagnosis influences the test result Sensitivity and Specificity Principles of Screening

  6. “The Square” Disease State + Sensitivity = A/(A+C) [TP/all those with disease] Specificity = D/(B+D) [TN/all those without disease] PPV = A/(A+B) [TP/all positives] NPV = D/(C+D) [TN/all negatives] - A True Positive B False Positive + Test Result D True Negative C False Negative -

  7. PPV True positive 100%-PPV False positive NPV True negative 100%-NPV False negative Test Result Diagnosis

  8. Sensitivity True positive 100%-Sensitivity False negative Specificity True negative 100%-Specificity False positive Test Result Diagnosis

  9. 96% sensitive 98% specific 50% sensitive 100% specific 100% sensitive 80% specific $20ºº WAR Sensitivity vs. Specificity Height

  10. Sensitivity vs. Specificity True Negative False Positive

  11. PPV = TP/(TP+FP) 2000 patients, ½ with a disease. Lab value discriminates 98% Specific 98% Sensitive 1000 1000 True Positives 980 20 PPV = 980/(980+20) PPV = 98% FP

  12. PPV = TP/(TP+FP) 2000 patients, ½o with a disease. Lab value discriminates 98% Specific 98% Sensitive 1900 100 True Positives 98 38 PPV = 98/(98+38) PPV = 72% FP

  13. Limiting the Test Population “Diagnostic” tests have a good PPV because we don’t use them indiscriminantly. If we did, false positives would increase, PPV would drop and the usefulness of the test would be lost 100 100 True Positives 98 2 PPV = 98/(98+2) PPV = 98% FP

  14. Screening 100000 10 True Positives 9 2000 PPV = 9/(9+2000) PPV = 0.4% FP

  15. False-negative “cost” $$ Cost of treating and caring for patient $$ Loss of “productive” member to society Emotional burden of living with a preventable condition Would like NO false negatives Fewer false negatives meansmore false positives False-positive “cost” $$ Cost of retesting $$ Cost of treatment and/or iatrogenic injury (if started) Emotional burden of the “sick-child” syndrome Sens and Spec with a good PPV Minimize False Negatives and False Positives

  16. What kind of things should be screened • Classically • Disorder is silent (no symptoms until irreversible damage done) (PKU) • Intervention is definitive (Diet prevents outcome) • Current Model • Disorder that can be clinically diagnosed but early diagnosis is advantageous (MSUD, CAH) • Intervention leads to improved outcome (HbSS) • Future (constant) consideration? • Can diagnose the currently untreatable • Opportunity for research, expanding the database • Genetic counseling …

  17. Lessons from history: THE PhenylKetonUria STORY…

  18. The PKU Story • 1934: Borgny Egeland presents Dr. Asbjörn Fölling with a urine sample (nwbws) • Isolated Phenylpyruvate • Still not sure of the physiologic link • But by 1959: shown that a low phenylalanine diet can improve outcome (case series). • Youngest seems to do best • Dr. Guthrie develops the “bacterial inhibition assay” • For testing blood levels on patients with PKU during therapy

  19. PKU: the first milestone • Dr. Guthrie takes his message to the streets • Bypassed medical community • Politicians • Looking for a magic bullet • Lots of money available • Presidents Advisory Committee • Popular Press • NY Times • Good Housekeeping • Emotional and popular push to institute state mandated universal newborn screening

  20. The PKU Story • 1963: Mandatory newborn screening begins in Massachusetts, then Maryland. • 1974: First systematic review of test accuracy • Found twice as many cases as expected • The problem of assumptions: • Some MR with hyperPhe all hyperPhe will get MR • Incidence of HyperPhe in the general “normal” population? Up to 20mg/dL can be “normal” • How many kids were picked up and treated unnecessarily? At what cost?

  21. PKU: the second milestone • 3 years without a hit in Wash DC • Quit testing? • Load other tests (cheap) • Payoff for 1:15000 to 1:1500 • By 1975, 43 states mandated screening, None mandated treatment. • Formula gross and expensive and not always reimbursed

  22. Lessons from the PKU story • Assumption about accuracy of test • FP/FN early on • Assumption about efficacy of treatment • 5 years vs. a lifetime • Does all hyperPhe need to be treated? • Early analysis focused on dollar-amount cost/benefit • Overly simplistic 50¢ to $100,000 • Didn’t account for setup costs • Didn’t account for FOLLOW-UP / TREATMENT

  23. Lessons from the PKU story • Overall feeling is positive, however • Dove in unprepared, but learned to swim as we went • Adjustments have been made • Some information lost to assumptions forever • “Sneaking” in the infrastructure and mandate makes adding tests VERY easy and cheap • Decreased costs  decreased perceived need to show benefit • Which is why we need to be reminded

  24. Lessons from history: THE Sickle Cell Story STORY…

  25. The HbSS Story • 1970s, Public Health Agencies, Physicians, African-American Activists, Federal and State governments, for unclear reasons, chose to implement mandatory sickle cell screening laws. • In retrospect, it was not clear what the laws were hoping to accomplish • Screened were kids and young adults • Already diagnosed, already “damaged” • No cure

  26. The HbSS Story • Lack of sensitivity to issues of race • Most early programs targeted “high-risk” population, ie: African-Americans. • NY State Law: all persons “not of the Caucasian, Indian, or Oriental races” be tested for sickle cell trait before being allowed to obtain a marriage license. • DC law referred to sickle cell disease as a “communicable disease.” • National focus on this “most vital health issue” took funds from other programs to fund sickle cell research.

  27. The HbSS Story • Controversy around accuracy and validity of early screening tests • Confusion about carrier vs. disease states • Carrier Status associated with: • Denial of health and life insurance • Denial of employment opportunities • Denial of acceptance into the Air Force academy • Boycotts of sickle cell screening programs were staged

  28. The HbSS Story • Inadequate protection of the patient’s rights • Rush to get laws into place left out protective clauses about • Result confidentiality • Competent genetic counseling • Adequate public education • Guaranteed medical benefits • Universal guidelines for quality control in labs

  29. The HbSS Story • 1980s found that newborn screening could lead to improved outcome through use of antibiotics and vaccines. • From 5% mortality at 2 years of age to <1% • Decrease in morbidity and mortality compared to historical cohort.

  30. The Maryland Newborn Screening Program

  31. Maryland • Second state to adopt state-wide newborn screening, after Mass. • Policies set by the “Advisory Council on Hereditary and Congenital Disorders.” • legislative, medical and consumer members • consumers are the majority

  32. Maryland • Council considers: • incidence • cost of treatment • public sentiment • opinions of affected individuals • opinions of psychological, social, ethical and economic “experts” • Informed consent • $15.75 per child, covers all tests

  33. Maryland • PKU 1965 • MSUD 1973 • Homocystinuria 1973 • Tyrosinemia 1973 • Hypothyroidism 1979 • Galactosemia 1981/1984 • Biotinidase Deficiency 1984 • HbSS 1985 • CAH 2001 • MCADD to be added (medium chain acyl-CoA dehydrogenase deficiency)

  34. Maryland Disorder Classic in MD Expected • PKU 1/ 12,712 1/ 15,000 • MSUD 1/103,466 1/120,000 • Homocystinuria 1/138,852 1/240,000 • Tyrosinemia 1/116,056 1/100,000 • Galactosemia 1/ 81,426 1/ 40,000 • Hypothyroidism 1/ 6,365 1/ 5,000 We’re #1!

  35. The Controversies • National vs. Regional control • Leftover Samples • Informed Consent vs. Dissent • MS/MS and DNA

  36. The Controversies • National vs. Regional control • Universal newborn screening for PKU, CH • Additional test mandated by states, sometimes for less than reasonable reasons • Very disparate screening programs • Different states have different incidence of disease based on population • Dr. Satcher’s equal access to care

  37. The Controversies • Leftover samples, (Maryland informs) • Linked (identifiable) • retesting, forensics • consent and concern for confidentiality • Unlinked (anonymous) • population studies: drug exposure, genes • QA and trying out new tests • right of refusal, concern for true unlinking • No reports of misuse, yet.

  38. The Controversies • Informed Consent vs. Dissent • State’s duty to protect it’s citizens vs. Parent’s duty to protect their child • NAS, 1975 (National Academy of Sciences) • Informed consent • IOM, 1994 (Institute of Medicine) • Mandatory offering • Informed consent • Task Force on Genetic Testing, 1997 • Informed consent, unless validity and utility of tests are established

  39. The Controversies • Informed Consent vs. Dissent • Wyoming and Maryland are only two states requiring informed consent. Mass for MS/MS • Maryland study • 5/1000 refused newborn screening • Most moms preferred to be asked prior to testing • Took less than 5 minutes of staff time • Hypothetical advantage for understanding f/u information including retesting.

  40. The Controversies • MS/MS and DNA testing • Testing all babies for all possible things • Charles P. Hehmeyer: malpractice lawyer • We knowingly kill or injure 1000 kids a year (by not screening) out of 4,000,000 (0.025%) • Convincing emotional argument, loose with numbers • March of Dimes: Any cost is worth it, [HbSS] Good of the many Good of the one

  41. The Controversies • MS/MS • good technology, fewer false positives • amino acids AND/OR acyl carnitines • limited ability to rationally use information, like PKU • Can pick up disease for which • We can “intervene,” don’t know how useful interventions are • We don’t know if we need to intervene • We can detect but don’t know if they exist in nature

  42. Things we do… • These are some examples of tests we use on a daily basis that evolved into routine practice before we knew how to interpret and act on the results. For the majority of patients we test, we’re still guessing. • Pulse-ox • Electronic Fetal Monitoring • Fetal pulse-ox • Newborn blood glucose • Home apnea monitors

  43. Things we do…

  44. Parent Refusal • “…is it true that a hospital can *make* you have a PKU test done? My mom talked me into getting [my son] a PKU test and I regretted it….it was awful seeing him in pain, and I ALREADY KNEW HE WAS JUST *F I N E*!!!” • “… just like the other mandatory newborn crap (immunizations, eye meds, etc).” • The natural screening model

  45. Parent Refusal • Reasons for refusal • Paranoia (justified or not) • See: HbSS screening • Leftover samples • Pain of Heelstick • +/- Incentive to develop less painful procedure given that it’s a requirement • Can supposedly be done

  46. Parent Refusal • “Sneaking” and “Intimidation” • When “reason” fails • Move to “SOP” and test baby “by accident” • Threaten that baby can’t leave hospital without test • “It’s the law” • Arguing about health care is like arguing about religion • Beliefs are deep and fundamental to the person’s identity • All states allow for informed parent refusal • Overall, poor form to resist a decision that’s as informed as it can be

  47. Summary (From the Task Force, 1997) • Infants should benefit from and be protected by newborn screening systems • Not all conditions are good candidates for screening • Should occur “often enough” to justify mass screening • Early treatment is effective, accepted and available • Test is simple, safe, valid, precise, acceptable • Screening is part of a system of follow-up, diagnosis, treatment and evaluation

  48. Summary • Infants born anywhere in the US should have access to screening tests that meet national standards and guidelines. • Data on validity and utility collected through pilot programs • Public screening programs should not be implemented until they have first demonstrated their value in well-conducted pilot studies

  49. Summary • Parents, on behalf of their children, have the right to • be informed about screening • refuse screening • confidentiality and privacy protections • Parents and consumers must be involved in all parts of the policy-making and implementation process

  50. Pitfalls of Newborn Screening • Assuming a negative (normal) result on a newborn screen definitively excludes the condition • false negatives are a given in any screening program • screening tests are NOT diagnostic tests, if you have suspicions about a disease, test for it

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