continuity clinic the exciting, emotional and often misunderstood world of
TRANSCRIPT
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
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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…
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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
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““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]
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DiagnosisDiagnosisDiagnosisDiagnosisTest ResultTest ResultTest ResultTest Result
False positiveFalse positive
True positiveTrue positive
True negativeTrue negative
False negativeFalse negative
100%-PPV100%-PPV
100%-NPV100%-NPV
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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 …
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The Virginia Newborn The Virginia Newborn Screening ProgramScreening Program
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Virginia Newborn Screening Services Virginia Newborn Screening Services Diagnosed Cases by Disorder 2002Diagnosed Cases by Disorder 2002
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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
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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
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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
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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!!!
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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.
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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)
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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.
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Congenital Congenital HypothyroidismHypothyroidism
The most common case example of the newborn screen at work
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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
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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
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Back to the BasicsBack to the Basics
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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
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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
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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!!!!!
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A sign for every office….A sign for every office….