Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international definition

Southern, Kevin W; Barben, Jürg; Gartner, Sílvia; Munck, À.; Castellani, Carlo; Mayell, Sarah; Davies, Jane C.; Winters, V.; Murphy, J.; Salinas, Danieli; McColley, Susanna A.; Ren, Clement L.; Farrell, Philip M.

doi:10.1016/j.jcf.2019.04.010

Cited by 50 publications

(40 citation statements)

References 14 publications

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“…of which has unclear phenotypic consequences [8,9]. Beyond technical and medical aspects, the choice of a NBS strategy is driven by the mutation spectrum in the screened population, the laboratory facilities, the health care system, the legal and economic aspects, and the acceptability by the population [10][11][12][13].…”

Section: Overview Of Newborn Screening Programsmentioning

confidence: 99%

“…These programs, however, lead to the detection of a high number of inconclusive cases, also referred to as Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) in Europe or CFTR-related metabolic syndrome (CRMS) in the US, compared to the number of CF cases [1,7]. The definition of CRMS/CFSPID includes infants with a sweat chloride value between 30-59 mmol/L and zero or one CF-causing variant, or a sweat chloride value below 30 mmol/L and two CFTR variants, at least one of which has unclear phenotypic consequences [8,9]. Beyond technical and medical aspects, the choice of a NBS strategy is driven by the mutation spectrum in the screened population, the laboratory facilities, the health care system, the legal and economic aspects, and the acceptability by the population [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

Bergougnoux

Lopez

Girodon

2020

IJNS

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There has been considerable progress in the implementation of newborn screening (NBS) programs for cystic fibrosis (CF), with DNA analysis being part of an increasing number of strategies. Thanks to advances in genomic sequencing technologies, CFTR-extended genetic analysis (EGA) by sequencing its coding regions has become affordable and has already been included as part of a limited number of core NBS programs, to the benefit of admixed populations. Based on results analysis of existing programs, the values and challenges of EGA are reviewed in the perspective of its implementation on a larger scale. Sensitivity would be increased at best by using EGA as a second tier, but this could be at the expense of positive predictive value, which improves, however, if EGA is applied after testing a variant panel. The increased detection of babies with an inconclusive diagnosis has proved to be a major drawback in programs using EGA. The lack of knowledge on pathogenicity and penetrance associated with numerous variants hinders the introduction of EGA as a second tier, but EGA with filtering for all known CF variants with full penetrance could be a solution. The issue of incomplete knowledge is a real challenge in terms of the implemention of NBS extended to many genetic diseases.

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Section: Overview Of Newborn Screening Programsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

Bergougnoux

Lopez

Girodon

2020

IJNS

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“…'Cystic fibrosis screen positive, inconclusive diagnosis' (CFSPID) is a designation given to infants with a positive NBS result, but not a definitive diagnosis of cystic fibrosis (CF). Evidence suggests the number who go on to develop some form of CF varies based on the NBS protocol, but at present, no clear indication can be given to parents about the likelihood that their child will develop CF, the type of CF, or when they might show symptoms [3]. Both the ECFS Neonatal Screening Working Group and the CFF have produced guidance on clinical management which stress the importance of clear communication [4,5].…”

Section: Introductionmentioning

confidence: 99%

Psychological Impact on Parents of an Inconclusive Diagnosis Following Newborn Bloodspot Screening for Cystic Fibrosis: A Qualitative Study

Johnson

Southern

Ulph

2019

IJNS

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Genetic results of uncertain clinical significance are being returned to parents following newborn screening, representing a paradigm change in how society considers health and illness. ‘Cystic Fibrosis screen positive, inconclusive diagnosis’ (CFSPID) is a designation given to newborns with a positive screening result for, but not a definitive diagnosis of, cystic fibrosis. We explored the psychological impact of receiving a CFSPID result on parents. Five semi-structured interviews were conducted with eight parents whose children have CFSPID. Interpretative phenomenological analysis identified these themes: “The way we were told”: ‘diagnosis as a traumatic event’ focused on how parents were distressed and dissatisfied by the initial screening result communication, ‘Facing and challenging traditional ideas about health and illness’ explored the emerging problem of how CFSPID does not fit the commonly accepted medical model, and ‘Making certainty out of uncertainty’ explored the varying strategies parents developed to adapt to the uncertainty regarding their child’s prognosis. Findings suggest that CFSPID results caused parents’ distress, initiated with the first communication of the result and persisting thereafter. Our data suggests approaches to the delivery of CFSPID results that may reduce the impact. Work is needed to close the gap between healthcare advances and societies commonly held medical model.

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“…The two most commonly used algorithms are IRT/IRT (analyzing the concentration of IRT in a second DBS specimen collected between 10-28 days of life, when the marker has greater specificity) and IRT/DNA (analyzing a panel of CFTR pathogenic variants in the initial DBS specimen) [11,12].The IRT/DNA protocol is probably the most widely used strategy and has the highest level of sensitivity, which provides good specificity [11,19]. However, using DNA analysis as part of a screening procedure leads to unwanted detection of CF carriers and inconclusive diagnoses [20,21]. Another limitation is that it does not offer equal coverage for all ethnic groups, so this strategy has certain legislative and ethical implications that should be assessed when including it into a neonatal screening program [22,23].Programs that use the IRT/IRT algorithm avoid the issue of carrier detection.…”

mentioning

confidence: 99%

“…The IRT/DNA protocol is probably the most widely used strategy and has the highest level of sensitivity, which provides good specificity [11,19]. However, using DNA analysis as part of a screening procedure leads to unwanted detection of CF carriers and inconclusive diagnoses [20,21]. Another limitation is that it does not offer equal coverage for all ethnic groups, so this strategy has certain legislative and ethical implications that should be assessed when including it into a neonatal screening program [22,23].…”

mentioning

confidence: 99%

Initial Evaluation of Prospective and Parallel Assessments of Cystic Fibrosis Newborn Screening Protocols in Eastern Andalusia: IRT/IRT versus IRT/PAP/IRT

Sadik¹,

Algaba

Jiménez

et al. 2019

IJNS

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Identifying newborns at risk for cystic fibrosis (CF) by newborn screening (NBS) using dried blood spot (DBS) specimens provides an opportunity for presymptomatic detection. All NBS strategies for CF begin with measuring immunoreactive trypsinogen (IRT). Pancreatitis-associated protein (PAP) has been suggested as second-tier testing. The main objective of this study was to evaluate the analytical performance of an IRT/PAP/IRT strategy versus the current IRT/IRT strategy over a two-year pilot study including 68,502 newborns. The design of the study, carried out in a prospective and parallel manner, allowed us to compare four different CF-NBS protocols after performing a post hoc analysis. The best PAP cutoff point and the potential sources of PAP false positive results in our non-CF newborn population were also studied. 14 CF newborns were detected, resulting in an overall CF prevalence of 1/4, 893 newborns. The IRT/IRT algorithm detected all CF cases, but the IRT/PAP/IRT algorithm failed to detect one case of CF. The IRT/PAP/IRT with an IRT-dependent safety net protocol was a good alternative to improve sensitivity to 100%. The IRT × PAP/IRT strategy clearly performed better, with a sensitivity of 100% and a positive predictive value (PPV) of 39%. Our calculated optimal cutoffs were 2.31 µg/L for PAP and 167.4 µg2/L2 for IRT × PAP. PAP levels were higher in females and newborns with low birth weight. PAP false positive results were found mainly in newborns with conditions such as prematurity, sepsis, and hypoxic-ischemic encephalopathy.

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Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international definition

Cited by 50 publications

References 14 publications

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

Psychological Impact on Parents of an Inconclusive Diagnosis Following Newborn Bloodspot Screening for Cystic Fibrosis: A Qualitative Study

Initial Evaluation of Prospective and Parallel Assessments of Cystic Fibrosis Newborn Screening Protocols in Eastern Andalusia: IRT/IRT versus IRT/PAP/IRT

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