Immunoreactive trypsinogen (IRT) as a biomarker for cystic fibrosis: Challenges in newborn dried blood spot screening

Therrell, Bradford L.; Hannon, W. Harry; Hoffman, Gary; Ojodu, Jelili; Farrell, Philip M.

doi:10.1016/j.ymgme.2012.02.013

Cited by 48 publications

(85 citation statements)

References 17 publications

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“…Lowering the cutoff to 49.4 ng/mL, which corresponds to the top fourth percentile used by many states, 4 would have resulted in 4 fewer cases being missed by the IRT step (or ,1 per year). The costs and inefficiencies to the program that would come with lowering the IRT cutoff value to the top fourth percentile (estimated by GDSP to be approximately twice the costs for mutation testing and genetic counseling for carriers and likely higher costs for additional referrals) are considered excessive compared with the small gain in sensitivity (1%-2%); they would also conflict with the program's goal of equally maximizing both sensitivity and specificity.…”

Section: Resultsmentioning

confidence: 99%

“…3 By 2010, NBS for CF had been instituted throughout the United States. 4 During development of NBS for CF in California (2000)(2001)(2002)(2003)(2004)(2005), the California Department of Public Health Genetic Disease Screening Program (GDSP) established 6 requirements and goals (Fig 1). One challenge that California faced was a poor understanding of common CFTR mutations within its large and heterogeneous population.…”

Section: What's Known On This Subjectmentioning

confidence: 99%

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Newborn Screening for Cystic Fibrosis in California

et al. 2015

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, on behalf of the California Cystic Fibrosis Newborn Screening Consortium abstract OBJECTIVES: This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California.METHODS: From July 16, 2007, to June 30, 2012, a total of 2 573 293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values $62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with $2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling.RESULTS: Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test-positive infants, respectively). CONCLUSIONS:The 3-step model had high detection and low false-positive levels in this diverse population. WHAT'S KNOWN ON THIS SUBJECT:Several newborn screening models for cystic fibrosis (CF) exist, including DNA-based models that use mutation panels. There is limited experience with models (such as used in California) that include comprehensive DNA sequence testing methods as part of newborn screening.WHAT THIS STUDY ADDS: California' s 3-step newborn screening model for CF showed high efficiency, sensitivity, and positive predictive value. More than 300 mutations were found, reflecting the state' s diverse population. Some CF transmembrane conductance regulator-related metabolic syndrome cases converted to CF over time.

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Section: Resultsmentioning

confidence: 99%

Section: What's Known On This Subjectmentioning

confidence: 99%

Newborn Screening for Cystic Fibrosis in California

et al. 2015

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“…However, not all screening programmes seem to have encountered such problems 14. In any case, false negatives in babies presenting with MI are not generally of concern, since these cases should always be thoroughly investigated for CF.…”

Section: Discussionmentioning

confidence: 99%

“…However, our data does not demonstrate a difference in the false positive rate pre and post the change to testing at day 5–8 (IRT—IRT protocol). The kits utilised at various stages may have affected the results, as there are various forms of IRT in blood that may react differently in the assays; however their relative merits are the subject of continuing debate 14 20. Between 1980 and 1990, as other centres adopted this screening strategy, poor interlaboratory performance in a quality assurance scheme highlighted problems related to the adaptation of the first generation of IRT radioimmunoassays for use with dried blood spots 21.…”

Section: Discussionmentioning

confidence: 99%

Thirty-years of screening for cystic fibrosis in East Anglia

et al. 2012

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The diagnosis of screen-positive babies proved difficult in a minority of cases with the classification of some patients changing with evolving phenotype. Our results illustrate the importance of collecting outcome data over a long time period for accurate assessment of the screening programme. This study provides evidence that newborn screening for CF is a valid undertaking that detects 95% of unsuspected CF cases presenting before 3 years of age.

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“…Cutoff values at 48 hours of life can be set in different ways: an absolute value, typically 60–65 ng/ml, although values up to 90–105 ng/ml are acceptable, or a changing value based on the results obtained over a period of time, which may be a day or a month, accepting values higher than the 90th, 95th or 98th percentiles for that period as pathological. All these findings have been summarized in an excellent review by Therrell Jr et al [15]. …”

Section: Introductionmentioning

confidence: 99%

Differences in immunoreactive trypsin values between type of feeding and ethnicity in neonatal cystic fibrosis screening: a cross-sectional study

Cortés

Roldán

Palazón‐Bru

et al. 2014

Orphanet J Rare Dis

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BackgroundWe studied the differences in immunoreactive trypsin (IRT) in neonatal screening for cystic fibrosis (CF) associated individually with the age of the newborn, ethnicity and environmental temperature. In this study, we determine the overall influence of environmental temperature at birth, gender, feeding, gestational age, maternal age and ethnic origin on an abnormal IRT result.MethodsCross-sectional observational study. A sample was selected of newborns from Alicante (Spain) who underwent neonatal CF screening in 2012–2013. Primary variable: abnormal IRT levels (≥65 ng/ml). Secondary variables: gender, maternal origin, maternal age (years) (<20, 20–40, >40), gestational age (weeks) (<32, 32–37, >37), type of feeding (natural, formula, mixed and special nutrition), >20 days from birth to blood collection, and average temperature during the month of birth (in°C). Using a multivariate logistic regression model the adjusted odds ratios (ORs) were estimated to analyze the association between atypical IRT levels and the study variables. The α error was 5% and confidence intervals (CI) were calculated for the most relevant parameters.ResultsOf a total of 13,310 samples, 199 were abnormal (1.34%). Significant associated factors: feeding method (natural → OR = 1; mixed → OR = 0.53, 95% CI: 0.31-0.89; formula → OR = 0.72, 95% CI: 0.48-1.07; special → OR = 21.88, 95% CI: 6.92-69.14; p < 0.001).ConclusionsNewborns receiving special nutrition have a 20-fold higher risk for abnormal IRT levels, and screening is advisable once normalized feeding is initiated. It is advisable to consider ethnic variability. Seasonality was not important.

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Immunoreactive trypsinogen (IRT) as a biomarker for cystic fibrosis: Challenges in newborn dried blood spot screening

Cited by 48 publications

References 17 publications

Newborn Screening for Cystic Fibrosis in California

Newborn Screening for Cystic Fibrosis in California

Thirty-years of screening for cystic fibrosis in East Anglia

Differences in immunoreactive trypsin values between type of feeding and ethnicity in neonatal cystic fibrosis screening: a cross-sectional study

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