PEDIATRICS Vol. 99 No. 6 June 1997, pp. 819-824
Newborn Screening for Cystic Fibrosis in Wisconsin: Comparison of Biochemical and Molecular Methods
Received Aug 6, 1996; accepted Oct 15, 1996.
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From the * Waisman Center for Mental Retardation and Human
Development; Departments of Pediatrics and Biostatistics, § State
Laboratory of Hygiene, University of Wisconsin-Madison, Madison,
Wisconsin, and the Medical College of Wisconsin, Milwaukee,
Wisconsin.
Objectives. To evaluate
neonatal screening for cystic fibrosis (CF), including study of the
screening procedures and characteristics of false-positive infants,
over the past 10 years in Wisconsin. An important objective evolving
from the original design has been to compare use of a single-tier
immunoreactive trypsinogen (IRT) screening method with that of a
two-tier method using IRT and analyses of samples for the most common
cystic fibrosis transmembrane regulator (CFTR) (
F508) mutation. We
also examined the benefit of including up to 10 additional CFTR
mutations in the screening protocol.
Methods. From 1985 to 1994, using either the IRT or
IRT/DNA protocol, 220 862 and 104 308 neonates, respectively, were
screened for CF. For the IRT protocol, neonates with an IRT 
180 ng/mL were considered positive, and the standard sweat chloride test was
administered to determine CF status. For the IRT/DNA protocol, samples
from the original dried-blood specimen on the Guthrie card of neonates
with an IRT 110 ng/mL were tested for the presence of the F508
CFTR allele, and if the DNA test revealed one or two F508 alleles, a
sweat test was obtained.
Results. Both screening procedures had very high
specificity. The sensitivity tended to be higher with the IRT/DNA
protocol, but the differences were not statistically significant. The
positive predictive value of the IRT/DNA screening protocol was 15.2%
compared with 6.4% if the same samples had been screened by the IRT
method. Assessment of the false-positive IRT/DNA population revealed
that the two-tier method eliminates the disproportionate number of infants with low Apgar scores and also the high prevalence of African-Americans identified previously in our study of newborns with
high IRT levels. We found that 55% of DNA-positive CF infants were
homozygous for F508 and 40% had one F508 allele. Adding analyses
for 10 more CFTR mutations has only a small effect on the sensitivity
but is likely to add significantly to the cost of screening.
Conclusions. Advantages of the IRT/DNA protocol over IRT analysis include improved positive predictive value, reduction of false-positive infants, and more rapid diagnosis with elimination of recall specimens.
Key words: cystic fibrosis, newborn screening, immunoreactive trypsinogen, population incidence, DNA testing.
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