The Exciting, Emotional and often Misunderstood World of

1. The Exciting, Emotional and often Misunderstood World of NEWBORN SCREENING

2. Objectives • Identify what makes a screening test effective and its limitations • Understand sensitivity, specificity, positive predictive value, and negative predictive value • Be familiar with the Virginia Newborn Screen • Know how to deal with a positive screening value for hypothyroidism

3. 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…

4. 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

5. “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 -

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

7. 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 …

8. The Virginia Newborn Screening Program

9. Virginia Newborn Screening Services Diagnosed Cases by Disorder 2002

10. 28 Items Screened in VA • Congenital Hypothyroidism (CH) • Medium-chain acyl-CoA dehydrogenase deficiency • Galactosemia • Congenital Adrenal Hyperplasia • Biotinidase Deficiency • Sickle Cell Anemia (Hb SS disease) • Maple syrup urine disease (MSUD) • Hemoglobin Sickle/Beta-Thal • Hemoglobin Sickle/C Disease • Homocystinuria • PKU Original tests prior to March 2006

11. Cystic Fibrosis Argininosuccinic aciduria Beta-Ketothiolase Deficiency Carnitine uptake Deficiency Citrullinemia Glutaric Acidemia type I Isovaleric Acidemia Long Chain hydroxyl-CoA Dehydrogenase Deficiency Methylmalonic acidemia (mutase deficiency) Methylmalonic acidemia Multiple carboxylase deficiency Propionic acidemia Tyrosinemia type I Trifunctional protein defic. Very long chain acyl-CoA dehydrogenase deficiency 3-hydroxy 3-methyl glutaric aciduria 3-methylcrotonyl-CoA carboxylase deficiency 28 Items Screened in VA NEW TESTS

12. 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

13. 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 suspecting a disease, test for it!!!

14. Pitfalls of Newborn Screening • Not 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.

15. Pitfalls of Newborn Screening • Not 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)

16. 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. • 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.

17. Congenital Hypothyroidism The most common case example of the newborn screen at work

18. Newborn Screen for Hypothyroidism • Thyroxine (T4) level is measured • If T4 level falls in lowest 10% of the results a TSH is measured on same specimen • An elevated TSH indicates primary hypothyroidism and the pediatrician is notified

19. Epidemiology • Most cases are sporadic – 10-15% are inherited defects • Inherited defects: usually autosomal recessive defects of thyroid hormone production • 1/3500-4000 newborns (in populations with normal iodine nutrition) • More common in hispanic and asian populations

20. Back to the Basics

21. Etiology • Thyroid Dysgenesis 1:4500 • Aplasia, hypoplasia, ectopy • Thyroid Dyshormonogenesis 1:30,000 • Hypothalamic-pituitary deficiency 1:100,000 • Transient * 1:200 • Thyroid-binding globulin deficiency 1:10,000 *common in areas of iodine deficiency; less common elsewhere and due to antithyroid drug in mom or transplacental thyroid-stimulating hormone antibodies

22. False Positives • Blood Transfusion – false elevation of FT4 and false depression of TSH • Premature infants – low FT4 as unable to mount TSH surge • Perinatal exposure to iodine – betadine during labor or use of iodine containing substance on cord

23. Newborn Screen • What do you do if TSH on screen is elevated? • Check serum TSH and FT4 to confirm  The test is a screen not a diagnostic test!!!!!

24. A sign for every office….