Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia

Sinclair, Graham; McMahon, V.; Schellenberg, Amy; Nelson, Tanya N.; Chilvers, Mark; Vallance, Hilary

doi:10.3390/ijns6020046

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…In particular, the initial and extended mutation panels used may not accurately reflect the wide array of disease-causing mutations encountered in an increasingly ethnically diverse population; the algorithm requires repeat testing at day 21 of life in a significant number of babies, resulting in stress for the family and an organisational cost for the service; a proportion of babies are reported as ‘probable carriers’, with resultant ambiguity for parents in a screening programme whose primary aim is not carrier detection. In addition, a normal second IRT result is associated with false negative cases in some children [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

A Public Dialogue to Inform the Use of Wider Genomic Testing When Used as Part of Newborn Screening to Identify Cystic Fibrosis

Kinsella¹,

Hopkins²,

Cooper³

et al. 2022

IJNS

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Cystic fibrosis (CF) has been included within the UK national newborn screening programme since 2007. The approach uses measures of immunoreactive trypsin (IRT) in dried blood spot samples obtained at day 5 of life. Samples which reveal IRT results >99.5th centile go on to be tested for a limited panel of CF mutations. While the programme works well and achieves a high level of sensitivity and specificity, it relies upon repeat testing in some cases and identifies probable carriers, both potentially provoking parental anxiety. In addition, the limited CF mutation panel may not fully reflect the ethnic diversity within the UK population. The use of wider genomic screening, made possible by next-generation sequencing to replace more limited panels, can be used to avoid these shortcomings. However, the way in which this approach is employed can either be designed to maximise specificity by limiting reporting to combinations of known pathogenic mutations or can maximise sensitivity by also reporting combinations of pathogenic mutations together with variants of uncertain significance. The latter approach also increases the number of Cystic Fibrosis Screen-Positive Inconclusive Diagnosis (CFSPID) designations reported, resulting in uncertainty for parents. To help consider the design of the programme, a dialogue was commissioned by the UK National Screening Committee (UKNSC) to elicit the views of members of the public without direct experience of CF, to determine if there was a preference for maximising the sensitivity or the specificity of CF screening. The participants initially expressed a clear preference to maximise sensitivity and avoid missing CF cases, but after time to reflect and consider the implications of their choice, a number changed their views so as to tolerate some missed cases if this resulted in greater certainty of outcome; this became the majority view. It is proposed that it may be a generalisable finding that the public, when facing whole-population screening programmes, may require significant time and information to inform and make their choices and may attach great importance to clarity and certainty of outcome in the screening process.

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Section: Introductionmentioning

confidence: 99%

A Public Dialogue to Inform the Use of Wider Genomic Testing When Used as Part of Newborn Screening to Identify Cystic Fibrosis

Kinsella¹,

Hopkins²,

Cooper³

et al. 2022

IJNS

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“…A 2020 study report on the clinical impact of NBS for CAH and the incremental costs in screened vs. unscreened newborns found that while NBS did not result in cost savings, it was cost effective since screened newborns were less likely to require medical transport and had shorter hospital stays resulting in lower hospitalization costs [ 372 ]. Another study reported in 2020 found that an IRT-DNA-IRT algorithm, with a repeat IRT measurement for apparent carriers at 21 days, successfully reduced the number of sweat tests required without significantly impacting CF case detection sensitivity [ 373 ]. Report of a program study in 2023 described the validation of a second-tier dual derivatization approach with LC-MS/MS to detect 2-methylcitric acid, methylmalonic acid, and total homocysteine in DBS cards amenable to NBS [ 374 ].…”

Section: Resultsmentioning

confidence: 99%

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Therrell,

Padilla,

Borrajo

et al. 2024

IJNS

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Newborn bloodspot screening (NBS) began in the early 1960s based on the work of Dr. Robert “Bob” Guthrie in Buffalo, NY, USA. His development of a screening test for phenylketonuria on blood absorbed onto a special filter paper and transported to a remote testing laboratory began it all. Expansion of NBS to large numbers of asymptomatic congenital conditions flourishes in many settings while it has not yet been realized in others. The need for NBS as an efficient and effective public health prevention strategy that contributes to lowered morbidity and mortality wherever it is sustained is well known in the medical field but not necessarily by political policy makers. Acknowledging the value of national NBS reports published in 2007, the authors collaborated to create a worldwide NBS update in 2015. In a continuing attempt to review the progress of NBS globally, and to move towards a more harmonized and equitable screening system, we have updated our 2015 report with information available at the beginning of 2024. Reports on sub-Saharan Africa and the Caribbean, missing in 2015, have been included. Tables popular in the previous report have been updated with an eye towards harmonized comparisons. To emphasize areas needing attention globally, we have used regional tables containing similar listings of conditions screened, numbers of screening laboratories, and time at which specimen collection is recommended. Discussions are limited to bloodspot screening.

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“…Obtaining false negative results for CF is more common than for other genetic disorders included in NBS panels, mainly due to the cut-offs used in NBS programs that use IRT as a marker, seasonal variations associated with temperature and analytical variables related to the performance of the reagent kits [30]. Additionally, the characteristics of the disease itself determine that individual biological variability is relevant because not all variants in the CFTR gene result in high levels of IRT [39], which may cause false negative results. In the present study we obtained that the 98.5 percentile of the distribution corresponded to 41 ng/ mL, a value below the cut-off level established for the program, that is why we would highly recommend adjusting a new cut-off value to decrease false negative results as low as possible.…”

Section: Discussionmentioning

confidence: 99%

Newborn Screening Program for Cystic Fibrosis in Cuba: Three Years’ Experience

Castells,

Sánchez,

Frómeta

et al. 2023

J. inborn errors metab. screen.

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In Cuba, newborn screening (NBS) for cystic fibrosis (CF) was introduced in January 2019. The results from the first three years of the CF NBS program are presented. An IRT/IRT protocol was followed using a cut-off value of 50 ng/mL. In this period 281,717 neonates were screened, 2,197 samples had increased IRT values, and a second sample was necessary (recall rate=0.78%). In 686 (0.24%) neonates, IRT was still elevated, and they were referred for clinical evaluation. Twenty-one children were confirmed by sweat test and molecular biology. Eighteen newborns presented variant F508del. A false negative case was reported. Demographic data of 32,764 neonates were collected. The average age of sampling was six days with results available at 11 days of life, but 1.7% of the samples were collected 20 days after birth. The mean IRT value was 12.7±11.7 ng/mL (ranging 0-283 ng/mL) with a calculated 98.5 percentile value of 42.4 ng/mL. On average, the samples were processed five days after collection and two days after they were received at the laboratory. Although CF NBS program in Cuba is just beginning, it can be predicted that CF will be one of the most frequent inherited-metabolic diseases in the Cuban population.

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Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia

Cited by 7 publications

References 23 publications

A Public Dialogue to Inform the Use of Wider Genomic Testing When Used as Part of Newborn Screening to Identify Cystic Fibrosis

A Public Dialogue to Inform the Use of Wider Genomic Testing When Used as Part of Newborn Screening to Identify Cystic Fibrosis

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Newborn Screening Program for Cystic Fibrosis in Cuba: Three Years’ Experience

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