Clinical evaluation of the Nanoduct sweat test system in the diagnosis of cystic fibrosis after newborn screening.

UNLABELLED: After a positive newborn screening test for cystic fibrosis (CF), a sweat test is performed to confirm the diagnosis. The success rate of the generally acknowledged methods (Macroduct/Gibson and Cooke) in newborns varies between 73 and 99%. The Nanoduct sweat test system is easier to perform and less sweat is needed. The main aim of this study was to measure the success rate of the Nanoduct compared to current approved sweat test methods in a newborn population. After informed consent of the parents, newborns with a positive screening test for CF were included. The Macroduct or Gibson and Cooke and Nanoduct were performed in all infants, during the same appointment. The chloride concentration was determined by standard coulorimetry; conductivity was measured directly and converted to a NaCl molarity. One hundred eight newborns were included: 17 with CF, 7 with cystic fibrosis transmembrane regulator (CFTR)-related metabolic syndrome (CRMS), and 84 healthy children. The success rate of the Nanoduct was 93% and for the Macroduct/Gibson and Cooke 79% (McNemar, p = 0.002). The Nanoduct detected the same CF patients as the Macroduct/Gibson and Cooke; one CF patient had an equivocal result for both tests, and no patients were missed. The area under the receiver operating characteristic curve for detection of CF with the Nanoduct was 0.999, with ideal cutoff levels of 91 and 66 mmol/l, comparable to former studies. CONCLUSION: The success rate of the Nanoduct to collect sufficient sweat in infants was higher compared to the Macroduct and Gibson and Cooke.

To know or not to know, disclosure of a newborn carrier screening test result for cystic fibrosis.

PURPOSE: Most newborn screening (NBS) strategies for Cystic Fibrosis (CF) also identify carriers. However, it is unclear if parents want to be informed about their child's carrier status or not. METHODS: Focus group discussions with pregnant couples to explore their opinions about disclosure of a carrier result for CF of their newborn. RESULTS: All (n = 30) wanted to be informed when newborn screening would show their newborn being a CF-carrier. Their main reason was the implication of this knowledge for further family planning. Other family members could be informed and children within the family could be tested. Parents stated they have the right to know, but others also expressed that the choice of not being informed should be offered as well. CONCLUSION: Most parents want to be informed when NBS for CF reveals that their child is a CF-carrier, but the choice of not being informed should also be offered.

The influence of sex, gestational age, birth weight, blood transfusion, and timing of the heel prick on the pancreatitis-associated protein concentration in newborn screening for cystic fibrosis.

BACKGROUND: Pancreatitis-associated protein (PAP) is currently discussed as a marker in newborn screening (NBS) for cystic fibrosis (CF). However, it is not known if PAP concentrations are influenced by sex, gestational age, birth weight, blood transfusion or time of collection and what this would mean for NBS for CF. METHODS: In 2008 all newborns in part of the Netherlands were screened for CF by an IRT/PAP protocol. PAP concentration was determined by the MucoPAP ELISA (DynaBio), which was modified to a Dissociation Enhanced Lanthanide Fluoroimmunoassay (DELFIA) method following a protocol of PerkinElmer. RESULTS: In healthy newborns, the median PAP concentration was 0.5 µg/l (Interquartile range (IQR 0.3-0.8) whereas this was 3.2 µg/l (IQR 2.0-12.5) in CF infants. PAP concentrations were lower in premature infants 0.94 and 0.91 times for 25 to 31 + 6 weeks GA and 32 to 36 + 6 weeks respectively. A higher PAP concentration was observed in low-birth-weight infants (<2500 gram)(p = 0.001), per 100 gram birth weight gained the PAP concentration decreased with 0.1 %. PAP levels were higher after a blood transfusion, the 95th percentile increased from 1.3 to 3.6 µg/l leading to a higher false-positive rate. The PAP concentration increased when newborn screening was performed more than 168 hours (day 7) after birth (ß = 1.63), the 95th percentile increased from 1.3-1.6 µg/l to 4.0 µg/l after 168 hours (72,874 newborns were screened). CONCLUSION: Sex, birth weight, and gestational age lead to small differences in PAP concentrations without consequences for the screening algorithm. However, blood transfusion as well as performance of the heel prick after 168 hours (7 days) lead to clinically significant higher PAP levels and to a higher risk on a false-positive screening test result.

Improving test properties for neonatal cystic fibrosis screening in the Netherlands before the nationwide start by May 1st 2011.

When new technical possibilities arise in health care, often attunement is needed between different actors from the perspectives of research, health care providers, patients, ethics and policy. For cystic fibrosis (CF) such a process of attunement in the Netherlands started in a committee of the Health Council on neonatal screening in 2005. In the balancing of pros and cons according to Wilson and Jungner criteria, the advantages for the CF patient were considered clear, even though CF remains a severe health problem with treatment. Nevertheless, screening was not started then, mainly since the specificity of the tests available at that time was considered too low. Many healthy infants would have been referred for sweat testing and much uncertainty would arise in their parents. Also the limited sensitivity for immigrants and the detection of less severe phenotypes and carriers were considered problematic. The Health Council recommended a pilot screening project which was subsequently performed in some provinces, leading to a 4-step protocol: IRT, PAP, screening for a CFTR mutation panel, and sequencing of the CFTR gene. This would lead to the identification of 23 cases of classical CF, two infants with less severe forms and 12 carriers per year in the Netherlands. Thus many CF patients can be diagnosed early, while limiting the number of referrals, the number of infants with less severe forms diagnosed and the number of carriers identified. Technical solutions were found to limit the ethical problems. A nationwide program using this four step protocol started by 1 May 2011.

Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study.

CONTEXT: Newborn screening for cystic fibrosis (CF) is included in many routine programmes but current strategies have considerable drawbacks, such as false-positive tests, equivocal diagnosis and detection of carriers. OBJECTIVE: To assess the test performance of two newborn screening strategies for CF. DESIGN, SETTING AND PARTICIPANTS: In 2008 and 2009, CF screening was added to the routine screening programme as a prospective study in part of The Netherlands. INTERVENTIONS: Two strategies were performed in all newborns. In the first strategy, concentrations of immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) were measured. In the second method, samples with IRT ≥60 µg/litre were analysed for 36 CFTR mutations, followed by sequencing when a single mutation was detected. Tests were positive only with two identified CFTR mutations. MAIN OUTCOME: Sensitivity, specificity and positive predictive value (PPV) of both screening strategies. RESULTS: 145,499 infants were screened. The IRT/PAP approach showed a sensitivity of 95.0%, a specificity of 99.897% and a PPV of 12.3%. Test properties for the IRT/DNA/sequencing strategy were respectively 100%, 100% and 64.9%. Combining both strategies (IRT/PAP/DNA/sequencing) led to a sensitivity of 95.0%, a specificity of 100% and a PPV of 87.5%. CONCLUSION: In conclusion, all strategies performed well. Although there was no statistically significant difference in test performance, the IRT/DNA/sequencing strategy detected one infant that was missed by IRT/PAP (/DNA/sequencing). IRT/PAP may be the optimal choice if the use of DNA technology must be avoided. If identification of carriers and equivocal diagnosis is considered an important disadvantage, IRT/PAP/DNA/sequencing may be the best choice.