This Commentary summarizes what the author has learned in 46 years of research on newborn screening (NBS) for cystic fibrosis (CF) combined with healthcare and public health practice. The original ...expectation was that screening for this relatively common, life-threatening genetic disorder would lead to consistently timely diagnoses in the neonatal period and be equitable. Unfortunately, this ambitious goal has not been achieved in the USA despite the availability of an excellent, although imperfect, 2-tiered screening test employing immunoreactive trypsinogen (IRT) and DNA analysis for pathogenic variants in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). In fact, variations in the quality of NBS programs, inconsistencies in their operations, and disparities in outcomes have been prominent features. The causes include leadership challenges and deficiencies among both CF centers and NBS labs; failures to form effective partnerships among CF centers and with NBS programs; relatively rapid implementation after 2005 with variable quality planning; misunderstandings and erroneous dogma about CF; data limitations regarding IRT, especially cutoff values, and CFTR genetics; tolerance of suboptimal protocols and false negative results; problems in dried blood spot collections plus a lack of transparency and national oversight; partial lack of readiness, qualifications, funding and/or willingness to innovate with floating IRT cutoffs and DNA/CFTR analyses; follow up challenges/deficiencies impairing timeliness, including sweat testing limitations; and published guidelines that are more descriptive than sufficiently critical and directive. But the lessons learned through uniquely intensive CF NBS research have been enlightening and guided the U.S. Cystic Fibrosis Foundation to nationwide quality improvement initiatives.
Objective Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene, continues to present diagnostic challenges. Newborn screening and an evolving ...understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. Study design To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. Results After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. Conclusions It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project ( http://www.cftr2.org/index.php ) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR - related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR - related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.
Abstract This study combined a variety of methods to determine the prevalence of cystic fibrosis in the European Union. The results of literature reviews, surveys, and registry analyses revealed a ...mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98.
Background
Newborn screening for cystic fibrosis (CF) has been underway universally in the United States for more than a decade, as well in most European countries, and algorithms have been evolving ...throughout this period with quality improvement projects as immunoreactive trypsinogen (IRT) determinations alone have been transformed to a 2‐tier strategy with DNA analyses.
Objective
To apply next generation sequencing (NGS) as a screening method to expand the DNA tier and identify substantially more variants in the CF transmembrane conductance regulator (CFTR) gene to enhance sensitivity and equity while minimizing incidental findings.
Design
Sequential evaluation and improvement plan in three phases using algorithm modifications coupled to statewide follow up and analysis of screening outcomes.
Results
After demonstrating feasibility in the first phase, we studied an IRT/NGS algorithm that included CFTR Variants with Varying Clinical Consequences (VVCCs). This revealed a high identification of CF patients with 2‐variants detected through screening, but for every CF case there were 1.4 with CF metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID). This led us to a third phase of improvement in which the VVCCs were eliminated except for R117H, resulting in 94% 2‐variant detection of patients and 0.44:1 ratio of CRMS/CFSPID to CF.
Conclusion
NGS can be used with IRT as an effective method of identifying infants at risk for CF without an appreciable increase in detection of carriers. Its potential added value includes facilitating equity, enhancing sensitivity and detecting more CF patients with 2‐variants during the screening process.
Heterozygous (carrier) status for an autosomal recessive condition is traditionally considered to lack significance for an individual's health, but this assumption has been challenged by a growing ...body of evidence. Carriers of several autosomal recessive disorders and some X-linked diseases are potentially at risk for the pathology manifest in homozygotes. This minireview provides an overview of the literature regarding health risks to carriers of two common autosomal recessive conditions on the Recommended Uniform Screening Panel: sickle cell disease sickle cell trait (SCT) and cystic fibrosis (CF). We also consider and comment on bioethical and policy implications for newborn blood screening (NBS). Health risks for heterozygotes, while relatively low for individuals, are often influenced by intrinsic (e.g., other genomic variants or co-morbidities) and extrinsic (environmental) factors, which present opportunities for personalized genomic medicine and risk counseling. They create a special challenge, however, for developing screening/follow-up policies and for genetic counseling, particularly after identification and reporting of heterozygote status through NBS. Although more research is needed, this minireview of the SCT and CF literature to date leads us to propose that blanket terms such as “healthy heterozygotes” or “unaffected carriers” should be superseded in communications about NBS results, in favor of a more nuanced paradigm of setting expectations for health outcomes with “genotype-to-risk.” In the molecular era of NBS, it remains clear that public health needs to become better prepared for the full range of applied genetics.
•Mendelian recessive conditions have traditionally been thought to spare the carriers.•A growing body of evidence challenges the prevailing dogma of healthy heterozygotes.•Research shows that people with sickle cell trait and CF carriers have disease risks.•Mothers of boys with X-linked adrenoleukodystrophy also have a high risk for disease.•Policies and practices in newborn screening need to adapt to deal with carrier risks.
Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized ...medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF.
During the past quarter century, the diagnosis and treatment of cystic fibrosis (CF) have been transformed by molecular sciences that initiated a new era with discovery of the cystic fibrosis ...transmembrane conductance regulator (CFTR) gene. The knowledge gained from that breakthrough has had dramatic clinical impact. Although once a diagnostic dilemma with long delays, preventable deaths, and irreversible pathology, CF can now be routinely diagnosed shortly after birth through newborn screening programs. This strategy of pre-symptomatic identification has eliminated the common diagnostic “odyssey” that was a failure of the healthcare delivery system causing psychologically traumatic experiences for parents. Therapeutic advances of many kinds have culminated in CFTR modulator treatment that can reduce the effects of or even correct the molecular defect in the chloride channel —the basic cause of CF. This astonishing advance has transformed CF care as described fully herein. Despite this impressive progress, there are challenges and controversies in the delivery of care. Issues include how best to achieve high sensitivity newborn screening with acceptable specificity; what course of action is appropriate for children who are identified through the unavoidable incidental findings of screening tests (CFSPID/CRMS cases and heterozygote carriers); how best to ensure genetic counseling; when to initiate the very expensive but life-saving CFTR modulator drugs; how to identify new CFTR modulator drugs for patients with non-responsive CFTR variants; how to adjust other therapeutic modalities; and how to best partner with primary care clinicians. Progress always brings new challenges, and this has been evident worldwide for CF. Consequently, this article summarizes the major advances of recent years along with controversies and describes their implications with an international perspective.
To conduct interviews with a multiyear sample of parents of infants found to have heterozygous status for sickle cell hemoglobinopathy or cystic fibrosis during newborn blood screening (NBS).
...Interviewers with clinical backgrounds telephoned parents, and followed a structured script that blended follow-up and research purposes. Recruiting followed several steps to minimize recruiting bias as much as possible for a NBS study.
Follow-up calls were conducted with parents of 426 infant carriers of sickle cell hemoglobinopathy, and 288 parents of cystic fibrosis carriers (34.8% and 49.6% of those eligible). Among these, 27.5% and 7.8% had no recollection of being informed of NBS results. Of those who recalled a provider explanation, 8.6% and 13.0% appraised the explanation negatively. Overall, 7.4% and 13.2% were dissatisfied with the experience of learning about the NSB result. Mean anxiety levels were low but higher in the sickle cell hemoglobinopathy group (P < .001). Misconceptions that the infant might get the disease were present in 27.5% and 7.8% of parents (despite zero actual risk for disease). Several of these data were significantly predicted by NBS result, health literacy, parental age, and race/ethnicity factors.
Patient-centered public health follow-up can be effective after NBS identifies carrier status. Psychosocial complications were uncommon, but harms were substantial enough to justify mitigation.
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