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

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 Genetics Autosomal 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 Pathology Most commonly causes by a deficiency of phenylalanine hydroxylase leading to an accumulation of phenylalanine, which impairs the development of the central nervous system Diagnosis Rarely 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. Treatment Dietary 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 ScreeningPrinciples of Screening Lessons from the History of Newborn ScreeningLessons from the History of Newborn Screening Some specifics about Maryland NBSSome specifics about Maryland NBS The Other Controversies in Newborn ScreeningThe Other Controversies in Newborn Screening Why the heck would anyone refuse newborn screening !?!Why the heck would anyone refuse newborn screening !?! Summary and closing points with referencesSummary and closing points with references Principles of ScreeningPrinciples of Screening Lessons from the History of Newborn ScreeningLessons from the History of Newborn Screening Some specifics about Maryland NBSSome specifics about Maryland NBS The Other Controversies in Newborn ScreeningThe Other Controversies in Newborn Screening Why the heck would anyone refuse newborn screening !?!Why the heck would anyone refuse newborn screening !?! Summary and closing points with referencesSummary and closing points with references

4. Principles of Screening What makes a test a screening test? –Diagnostic test used to establish diagnosis PROBABLY have probablyDON’T have –Screening test used to distinguish those who PROBABLY have the disorder from those who probably DON’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. Principles of Screening 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

6. “The Square” A True Positive B False Positive C False Negative D True Negative 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]

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

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

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

10. Sensitivity vs. Specificity True Negative False Positive

11. PPV = TP/(TP+FP) True Positives FP 980 20 PPV = 980/(980+20) PPV = 98% PPV = 980/(980+20) PPV = 98% 1000 2000 patients, ½ with a disease. Lab value discriminates 98% Specific98% Sensitive

12. True Positives FP 98 38 PPV = 98/(98+38) PPV = 72% PPV = 98/(98+38) PPV = 72% 1900 100 2000 patients, ½ o with a disease. Lab value discriminates 98% Specific98% Sensitive PPV = TP/(TP+FP)

13. Limiting the Test Population True Positives FP 98 2 PPV = 98/(98+2) PPV = 98% PPV = 98/(98+2) PPV = 98% 100 “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

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

15. Sens and Spec with a good PPV False-negativeFalse-negative “cost” –$$ Cost of treating and caring for patient –$$ Loss of “productive” member to society –Emotional burden of living with a preventable condition NOWould like NO false negatives False-negativeFalse-negative “cost” –$$ Cost of treating and caring for patient –$$ Loss of “productive” member to society –Emotional burden of living with a preventable condition NOWould like NO false negatives meansmoreFewer false negatives means more false positives False-positiveFalse-positive “cost” –$$ Cost of retesting –$$ Cost of treatment and/or iatrogenic injury (if started) –Emotional burden of the “sick-child” syndrome meansmoreFewer false negatives means more false positives False-positiveFalse-positive “cost” –$$ Cost of retesting –$$ Cost of treatment and/or iatrogenic injury (if started) –Emotional burden of the “sick-child” syndrome 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: PKU 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 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 FOLLOW-UP / TREATMENT –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: SC 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 PKU1965 MSUD1973 Homocystinuria1973 Tyrosinemia1973 Hypothyroidism1979 Galactosemia1981/1984 Biotinidase Deficiency1984 HbSS1985 CAH2001 MCADDto be added (medium chain acyl-CoA dehydrogenase deficiency)

34. Maryland Disorder Classic in MDExpected PKU1/ 12,7121/ 15,000 MSUD1/103,4661/120,000 Homocystinuria1/138,8521/240,000 Tyrosinemia1/116,0561/100,000 Galactosemia1/ 81,4261/ 40,000 Hypothyroidism1/ 6,3651/ 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)Leftover samples, ( Maryland informs) –Linked (identifiable) retesting, forensicsretesting, forensics consent and concern for confidentialityconsent and concern for confidentiality –Unlinked (anonymous) population studies: drug exposure, genespopulation studies: drug exposure, genes QA and trying out new testsQA and trying out new tests right of refusal, concern for true unlinkingright 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]March of Dimes: Any cost is worth it, [HbSS] Good of the many Good of the one 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 evaluationScreening 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 conditionAssuming a negative (normal) result on a newborn screen definitively excludes the condition –false negatives are a given in any screening program NOT –screening tests are NOT diagnostic tests, if you have suspicions about a disease, test for it

51. Pitfalls of Newborn Screening Not collecting newborn screening sample prior to transfusion because the baby is “too young” or has not yet been fedNot collecting newborn screening sample prior to transfusion because the baby is “too young” or has not yet been fed –Transfusions and feeding history alter results of some, but not all of the newborn screening tests. –Card has place to list transfusions, time of first feeding, antibiotics, overall health and birthweight. Meaningful interpretation of test results takes all those bits of information into account.

52. Pitfalls of Newborn Screening Not collecting an adequate newborn screening sampleNot collecting an adequate newborn screening sample –Most newborn screening tests are quantitative. More or less blood means higher or lower values and may lead to false positives or negatives. Diagrams of correct circle filling are meant to ensure that the appropriate amount of blood is on the filter paper, and that there is no evidence of dilution (with alcohol, for example)

53. Pitfalls of Newborn Screening Assuming that an abnormal newborn screen is a false positive because the baby is well and/or because factors known to be associated with a false positive are present.Assuming that an abnormal newborn screen is a false positive because the baby is well and/or because factors known to be associated with a false positive are present. BEFORE –This runs counter to the whole purpose of newborn screening, which is to pick up kids BEFORE they are symptomatic –Typical cases: CH in a preterm infant: often false positives (low T4 then high TSH), but they MAY have it. Checking TFTs is prudent. Galactosemia: prematurity, heat-damage, TPN, or antibiotics may lead to FP. Therapy while awaiting confirmation is easy (lactose-free) but may interfere with breast-feeding.

54. Questions? Comments? Criticisms? Anything? Selected References: Newborn Screening Fact Sheets, Committee on Genetics, PEDIATRICS 98(3), Sep 1996, 473-501 - summary of metabolic diseases and issues around screening, diagnosing and management Serving the Family from Birth to the Medical Home, PEDIATRICS 106(2), Aug 2000, 389-426 - summary of historical, ethical and practical issues with a call for national standards Using Tandem Mass Spec for Metabolic Disease Screening Among Newborns - http//www.cdc.gov/mmwr/preview/mmwrthml/rr5003a1.htm Tyler for Life: http://www.tylerforlife.com/ - a nice web site for parents who want to know more about screening Selected References: Newborn Screening Fact Sheets, Committee on Genetics, PEDIATRICS 98(3), Sep 1996, 473-501 - summary of metabolic diseases and issues around screening, diagnosing and management Serving the Family from Birth to the Medical Home, PEDIATRICS 106(2), Aug 2000, 389-426 - summary of historical, ethical and practical issues with a call for national standards Using Tandem Mass Spec for Metabolic Disease Screening Among Newborns - http//www.cdc.gov/mmwr/preview/mmwrthml/rr5003a1.htm Tyler for Life: http://www.tylerforlife.com/ - a nice web site for parents who want to know more about screening