Transcript The Exciting, Emotional and often Misunderstood World of Bill Lefkowitz December-ish 2001 PKU (Phenylketonuria) Disorder of phenylalanine hydroxylation leading to accumulation of this amino.

The Exciting, Emotional and often
Misunderstood World of
Bill Lefkowitz
December-ish 2001
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.
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
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 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…
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
“The Square”
Sensitivity =
A/(A+C)
[TP/all those with disease]
A
B
True
Positive
False
Positive
Specificity =
D/(B+D)
[TN/all those without disease]
PPV =
C
D
[TP/all positives]
False
Negative
True
Negative
NPV =
[TN/all negatives]
A/(A+B)
D/(C+D)
Test Result
Diagnosis
True positive
False positive
True negative
False negative
Test Result
True positive
False negative
True negative
False positive
Diagnosis
Sensitivity vs. Specificity
96%
50% sensitive
100%
Height
WAR
$20ºº
100%
98%
80% specific
Sensitivity vs. Specificity
True Negative
False Positive
PPV = TP/(TP+FP)
2000 patients, ½ with a disease. Lab value discriminates
98% Specific
98% Sensitive
1000
1000
980 True Positives
PPV = 980/(980+20)
PPV = 98%
20 FP
PPV = TP/(TP+FP)
2000 patients, ½o with a disease. Lab value discriminates
98% Specific
98% Sensitive
1900
100
98 True Positives
PPV = 98/(98+38)
PPV = 72%
38 FP
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
98 True Positives
PPV = 98/(98+2)
PPV = 98%
2 FP
Screening
100000
10
9 True Positives
PPV = 9/(9+2000)
PPV = 0.4%
2000 FP
Sens and Spec with a good PPV
Minimize False Negatives and False Positives
• 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
means more false
positives
• False-positive “cost”
– $$ Cost of retesting
– $$ Cost of treatment
and/or iatrogenic injury (if
started)
– Emotional burden of the
“sick-child” syndrome
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 …
Lessons from history:
THE PhenylKetonUria STORY…
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
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
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?
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
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
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
Lessons from history:
THE Sickle Cell Story STORY…
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
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.
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
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
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.
The Maryland Newborn
Screening Program
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
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
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)
Maryland
•
•
•
•
•
•
Disorder
PKU
MSUD
Homocystinuria
Tyrosinemia
Galactosemia
Hypothyroidism
Classic in MD
1/ 12,712
1/103,466
1/138,852
1/116,056
1/ 81,426
1/ 6,365
We’re #1!
Expected
1/ 15,000
1/120,000
1/240,000
1/100,000
1/ 40,000
1/ 5,000
The Controversies
•
•
•
•
National vs. Regional control
Leftover Samples
Informed Consent vs. Dissent
MS/MS and DNA
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
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.
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
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.
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
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
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
Things we do…
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
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
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
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
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
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
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
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.
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)
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.
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