Continuity Clinic

The Exciting, Emotional and often The Exciting, Emotional and often Misunderstood World ofMisunderstood World of

Continuity Clinic

ObjectivesObjectives• 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

Continuity Clinic

Principles of ScreeningPrinciples of Screening• What makes a test a screening test?

– Diagnostic test used to establish diagnosis– Screening test used to distinguish those who

PROBABLYPROBABLY have have the disorder from those who probablyprobably DON’TDON’T have have the disorder

– A “A “POSITIVEPOSITIVE” screening test must be followed ” screening test must be followed up by a definitive diagnostic test! up by a definitive diagnostic test!

– It’s not the test, it’s how you use it…

Continuity Clinic

Principles of ScreeningPrinciples 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

Continuity Clinic

““The Square”The Square”

AA

True True PositivePositive

BB

False False PositivePositive

CC

False False NegativeNegative

DD

True True NegativeNegative

SensitivitySensitivity = = A/(A+C)A/(A+C)[TP/all those with disease]

SpecificitySpecificity = = D/(B+D)D/(B+D)[TN/all those without disease]

PPVPPV = = A/(A+B)A/(A+B)[TP/all positives]

NPV NPV == D/(C+D)D/(C+D)[TN/all negatives]

Continuity Clinic

DiagnosisDiagnosisDiagnosisDiagnosisTest ResultTest ResultTest ResultTest Result

False positiveFalse positive

True positiveTrue positive

True negativeTrue negative

False negativeFalse negative

100%-PPV100%-PPV

100%-NPV100%-NPV

Continuity Clinic

What kind of things should be What kind of things should be screenedscreened

• 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 …

Continuity Clinic

The Virginia Newborn The Virginia Newborn Screening ProgramScreening Program

Continuity Clinic

Virginia Newborn Screening Services Virginia Newborn Screening Services Diagnosed Cases by Disorder 2002Diagnosed Cases by Disorder 2002

Continuity Clinic

28 Items Screened in VA28 Items Screened in VA1. Congenital Hypothyroidism (CH)2. Medium-chain acyl-CoA dehydrogenase deficiency3. Galactosemia4. Congenital Adrenal Hyperplasia5. Biotinidase Deficiency6. Sickle Cell Anemia (Hb SS disease)7. Maple syrup urine disease (MSUD)8. Hemoglobin Sickle/Beta-Thal9. Hemoglobin Sickle/C Disease10. Homocystinuria11. PKU

Original tests

prior to

March 2006

Continuity Clinic

28 Items Screened in VA28 Items Screened in VA12. Cystic Fibrosis13. Argininosuccinic aciduria14. Beta-Ketothiolase Deficiency15. Carnitine uptake Deficiency16. Citrullinemia17. Glutaric Acidemia type I18. Isovaleric Acidemia19. Long Chain hydroxyl-CoA

Dehydrogenase Deficiency20. Methylmalonic acidemia

(mutase deficiency)

21. Methylmalonic acidemia22. Multiple carboxylase

deficiency23. Propionic acidemia24. Tyrosinemia type I25. Trifunctional protein defic.26. Very long chain acyl-CoA

dehydrogenase deficiency27. 3-hydroxy 3-methyl glutaric

aciduria28. 3-methylcrotonyl-CoA

carboxylase deficiency

NEW TESTS

Continuity Clinic

SummarySummary• 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

Continuity Clinic

Pitfalls of Newborn ScreeningPitfalls of Newborn Screening

• Assuming a negative (normal) result on Assuming a negative (normal) result on a newborn screen definitively excludes a newborn screen definitively excludes the conditionthe condition– false negatives are a given in any screening

program– screening tests are NOTNOT diagnostic tests - if

suspecting a disease, test for it!!!

Continuity Clinic

Pitfalls of Newborn ScreeningPitfalls of Newborn Screening

• Not collecting newborn screening Not collecting newborn screening sample prior to transfusion because the sample prior to transfusion because the baby is “too young” or has not yet been baby is “too young” or has not yet been fedfed– 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.

Continuity Clinic

Pitfalls of Newborn ScreeningPitfalls of Newborn Screening

• Not collecting an adequate newborn Not collecting an adequate newborn screening samplescreening 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)

Continuity Clinic

Pitfalls of Newborn ScreeningPitfalls of Newborn Screening• Assuming that an abnormal newborn screen Assuming that an abnormal newborn screen

is a false positive because the baby is well is a false positive because the baby is well and/or because factors known to be and/or because factors known to be associated with a false positive are present.associated with a false positive are present.– This runs counter to the whole purpose of newborn

screening, which is to pick up kids BEFOREBEFORE 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.

Continuity Clinic

Congenital Congenital HypothyroidismHypothyroidism

The most common case example of the newborn screen at work

Continuity Clinic

Newborn Screen for Newborn Screen for HypothyroidismHypothyroidism

• 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

Continuity Clinic

EpidemiologyEpidemiology• 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

Continuity Clinic

Back to the BasicsBack to the Basics

Continuity Clinic

EtiologyEtiology• Thyroid Dysgenesis 1:4500

– Aplasia, hypoplasia, ectopy

• Thyroid Dyshormonogenesis 1:30,000• Hypothalamic-pituitary deficiency 1:100,000• Transient * 1:200• Thyroid-binding globulin deficiency1:10,000

*common in areas of iodine deficiency; less common elsewhere and due to antithyroid drug in mom or transplacental thyroid-stimulating hormone antibodies

Continuity Clinic

False PositivesFalse 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

Continuity Clinic

Newborn ScreenNewborn 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!!!!!

Continuity Clinic

A sign for every office….A sign for every office….