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Philip M Farrell - One of the best experts on this subject based on the ideXlab platform.
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challenges in cystic fibrosis newborn screening and recommendations for primary care physicians
Pediatrics, 2015Co-Authors: Patrick R. Sosnay, Philip M FarrellAbstract:* Abbreviations: CF — : cystic fibrosis CFTR — : cystic fibrosis transmembrane conductance regulator gene CFTR2 — : Clinical and Functional Translation of CFTR CRMS — : CFTR-related metabolic syndrome NBS — : newborn screening During the past decade, newborn screening (NBS) for cystic fibrosis (CF) has disseminated worldwide after endorsements by the Centers for Disease Control and Prevention and the CF Foundation. Similar to widespread introduction of other NBS programs, CF NBS implementation occurred on a region-by-region basis by using a wide variety of screening strategies and analytical methods. All strategies begin with measurement of the biomarker, Immunoreactive Trypsinogen, and should end with a sweat chloride test.1 Although these protocol variations have differing screening efficiency or effectiveness, all CF NBS programs have provided a better opportunity for healthier outcomes than traditional strategies that rely on signs/symptoms for triggering the diagnostic processes associated with delays and discrimination.2 In an ambitious effort to optimize CF NBS for their region’s diverse population, California analyzed and planned their strategy over 2 years, leading to specific goals.3 In essence, California organized a strategy that applied cystic fibrosis transmembrane conductance regulator gene ( CFTR ) sequencing for the first time, required detection of 2 mutations for designation of positive screening, and recommendation of a sweat chloride test. This NBS method relies heavily on the interpretation of CFTR variants, as not every CFTR genetic change will result in CF. CF began as, and remains, a clinical diagnosis. The recognition of the Mendelian inheritance of a well-characterized phenotype allowed the detection of the gene responsible for CF, and of common mutations. These mutations (mostly European derived) were the basis for early CF genetic tests used for diagnosis and screening.4,5 However, as recognition of CF widened, and knowledge of the CF phenotype expanded to include milder and atypical phenotypes, testing for just the common mutations proved inadequate. Carrier screening … Address correspondence to Philip M. Farrell, MD, PhD, Departments of Pediatrics and Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, 600 Highland Ave, Madison, WI 53726. E-mail: pmfarrell{at}wisc.edu
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Immunoreactive Trypsinogen irt as a biomarker for cystic fibrosis challenges in newborn dried blood spot screening
Molecular Genetics and Metabolism, 2012Co-Authors: Bradford L Therrell, Harry W Hannon, Gary S Hoffman, Jelili Ojodu, Philip M FarrellAbstract:On May 23-24, 2011, a workshop entitled "Immunoreactive Trypsinogen (IRT) as a Biomarker for Cystic Fibrosis: Technical Issues and Challenges" was held in Annapolis, Maryland. The two-day workshop was co-hosted by the National Newborn Screening and Genetics Resource Center, Austin, Texas, and the Association of Public Health Laboratories, Silver Spring, Maryland, in collaboration with the Health Resources and Services Administration and the Centers for Disease Control and Prevention. Participants included nearly 40 representatives from U.S. state public health and commercial laboratories performing newborn dried blood spot screening tests for cystic fibrosis (CF), the federal government, academic research institutions, and commercial vendors of products used in newborn screening. Representatives from selected European CF newborn screening programs were also present. The workshop focused on identifying key IRT testing issues and mechanisms for achieving their resolution and laboratory harmonization in order to reduce, or eliminate completely, the late identified CF cases following a negative newborn screen. Informative findings are reported, their impacts on improving IRT screening are described, and their implications are discussed.
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a decision tree approach to cost comparison of newborn screening strategies for cystic fibrosis
Pediatrics, 2012Co-Authors: Janelle Wells, Gary S Hoffman, Marjorie A Rosenberg, Michael Anstead, Philip M FarrellAbstract:OBJECTIVE: Because cystic fibrosis can be difficult to diagnose and treat early, newborn screening programs have rapidly developed nationwide but methods vary widely. We therefore investigated the costs and consequences or specific outcomes of the 2 most commonly used methods. METHODS: With available data on screening and follow-up, we used a simulation approach with decision trees to compare Immunoreactive Trypsinogen (IRT) screening followed by a second IRT test against an IRT/DNA analysis. By using a Monte Carlo simulation program, variation in the model parameters for counts at various nodes of the decision trees, as well as for costs, are included and applied to fictional cohorts of 100 000 newborns. The outcome measures included the numbers of newborns given a diagnosis of cystic fibrosis and costs of screening strategy at each branch and cost per newborn. RESULTS: Simulations revealed a substantial number of potential missed diagnoses for the IRT/IRT system versus IRT/DNA. Although the IRT/IRT strategy with commonly used cutoff values offers an average overall cost savings of $2.30 per newborn, a breakdown of costs by societal segments demonstrated higher out-of-pocket costs for families. Two potential system failures causing delayed diagnoses were identified relating to the screening protocols and the follow-up system. CONCLUSIONS: The IRT/IRT screening algorithm reduces the costs to laboratories and insurance companies but has more system failures. IRT/DNA offers other advantages, including fewer delayed diagnoses and lower out-of-pocket costs to families. * Abbreviations: CF — : cystic fibrosis CFTR — : cystic fibrosis transmembrane conductance regulator IRT — : Immunoreactive Trypsinogen NBS — : newborn screening
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clarification of laboratory and clinical variables that influence cystic fibrosis newborn screening with initial analysis of Immunoreactive Trypsinogen
Pediatrics, 2009Co-Authors: Molly Kloosterboer, Gary Hoffman, Michael G. Rock, William M. Gershan, Anita Laxova, Philip M FarrellAbstract:OBJECTIVES. To ensure that each newborn receives an equitable test of the highest possible sensitivity, we recognized the necessity to reassess Immunoreactive Trypsinogen and DNA issues in cystic fibrosis newborn screening algorithms. Our objectives included clarification of various factors that influence Immunoreactive Trypsinogen concentrations and resolution of long-standing questions about variations in Immunoreactive Trypsinogen levels among newborns. METHODS. Immunoreactive Trypsinogen data on 660443 newborns who were born between July 1, 1994, and June 30, 2004, were abstracted from the Wisconsin State Laboratory of Hygiene databases and deidentified for analysis. Using a compiled data set, we analyzed various demographic characteristics to determine their role, if any, in Immunoreactive Trypsinogen variation. Specifically, season of birth, reagent lot, and birth weight were examined. Sensitivities of the most common cystic fibrosis newborn screening protocols, namely Immunoreactive Trypsinogen/Immunoreactive Trypsinogen and Immunoreactive Trypsinogen/DNA, were also investigated. RESULTS. Mean and 95th percentile Immunoreactive Trypsinogen levels were shown to vary by both season and reagent lot number and affect sensitivity of the assay. Low birth weight infants had significantly higher Immunoreactive Trypsinogen values than normal birth weight infants. Sensitivities were also found to vary on the basis of the algorithm used, with the highest sensitivity of 96.2% calculated for an Immunoreactive Trypsinogen/DNA protocol with 23 cystic fibrosis transmembrane conductance regulator mutation analyses compared with 80.2% with the Immunoreactive Trypsinogen/Immunoreactive Trypsinogen method used in 9 states. CONCLUSIONS. Floating, rather than fixed, cutoff values for the initial Immunoreactive Trypsinogen portion of any cystic fibrosis newborn screening protocol are generally necessary on the basis of the seasonal and reagent lot variations observed. Because of its lower sensitivity, Immunoreactive Trypsinogen/Immunoreactive Trypsinogen does not optimize detection of patients with cystic fibrosis.
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newborn screening for cystic fibrosis in wisconsin nine year experience with routine Trypsinogen dna testing
The Journal of Pediatrics, 2005Co-Authors: Michael J. Rock, Gary Hoffman, Ronald H. Laessig, Greg J Kopish, Thomas J Litsheim, Philip M FarrellAbstract:Objective To describe the development and follow-up confirmatory results of the routine cystic fibrosis (CF) newborn screening (NBS) program in Wisconsin. Methods CF NBS has been performed on a routine clinical basis in Wisconsin since July 1994. The 2-tiered Immunoreactive Trypsinogen (IRT)/DNA technique was used on dried blood on filter paper spots. From July 1994 to February 2002, mutation analysis was for the ΔF508 allele. Beginning in March 2002, multimutation analysis of 25 CF mutations was performed. Infants with a positive result on NBS were seen in certified CF centers for sweat testing by means of quantitative pilocarpine iontophoresis, and families received genetic counseling. Results From July 1994 to February 2002, there were 120 cases of CF detected by means of NBS (509,794 infants screened), with 53 ΔF508 homozygotes and 67 compound heterozygotes. There were 8 clinically diagnosed cases of CF (no ΔF508 allele). The CF incidence was 1:3983 (95%CI, 1:3373-1:4774). From March 2002 to June 2003, multimutation analysis identified 21 cases of classic CF (90,142 infants screened). Sweat tests were successfully performed in infants younger than 1 month. Conclusions Early diagnosis of CF through NBS was successfully performed, with an estimated sensitivity rate of 99% using the IRT/25 CFTR multimutation assay.
Carlo Castellani - One of the best experts on this subject based on the ideXlab platform.
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Immunoreactive Trypsinogen levels in newborn screened infants with an inconclusive diagnosis of cystic fibrosis
BMC Pediatrics, 2019Co-Authors: Carlo Castellani, Chee Y. Ooi, Rosie Sutherland, Katherine Keenan, Margaret Boland, Joe Reisman, Candice L. Bjornson, Mark A. Chilvers, Richard Van WylickAbstract:Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID). These infants have an uncertain long-term outcome and it is currently unclear around time of diagnosis, which infants are at higher risk of later fulfilling a CF diagnosis. In this study, we hypothesised that Immunoreactive Trypsinogen (IRT) levels, used in NBS as a marker of pancreatic disease and function, may reflect the degree of CFTR dysfunction in each individual and therefore would help to identify those with CRMS/CSPID who are later at risk for meeting the criteria of CF. In this longitudinal, prospective study, infants with CRMS/CFSPID and CF were recruited and followed in 9 CF clinics (Canada and Italy). We compared NBS IRT levels between CF and CRMS/CFSPID, and between children with CRMS/CFSPID→CF and CRMS/CFSPID→CRMS/CFSPID during the period of June 2007 to April 2016. Ninety eight CRMS/CFSPID and 120 CF subjects were enrolled. During the study period, 14 (14.3%) CRMS/CFSPID subjects fulfilled the diagnostic criteria for CF (CRMS/CFSPID→CF), while the diagnosis remained uncertain (CRMS/CFSPID→ CRMS/CFSPID) in 84 (85.7%) subjects. Significantly higher NBS IRT concentrations (ng/ml) were present in CF than CRMS/CFPSID (median (interquartile range): 143.8 (99.8–206.2) vs. 75.0 (61.0–105.9); P < 0.0001). Infants with CRMS/CFSPID→CF (n = 14) had significantly higher NBS IRT concentrations (ng/ml) than CRMS/CFSPID→ CRMS/CFSPID (n = 83) (median (interquartile range): 108.9 (72.3–126.8) vs. 73.7(60.0–96.0); P = 0.02). Amongst infants who tested positive on NBS for CF, there is a gradation of elevated NBS IRT concentrations. Infants with CF have higher NBS IRT levels than CRMS/CFPSID, and higher NBS IRT concentrations were present in infants with CRMS/CFSPID→CF than CRMS/CFSPID→ CRMS/CFSPID. NBS IRT concentrations, in concert with other factors, may have the potential to predict the likelihood of CF amongst infants with CRMS/CFSPID.
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Newborn screening for cystic fibrosis.
The Lancet. Respiratory medicine, 2016Co-Authors: Carlo Castellani, John Massie, Marci K. Sontag, Kevin W. SouthernAbstract:Since the late 1970s when the potential of the Immunoreactive Trypsinogen assay for early identification of infants with cystic fibrosis was first recognised, the performance of newborn blood spot screening (NBS) has been continually assessed and its use has gradually expanded. NBS for cystic fibrosis is a cost-effective strategy and, if standards of care are fully implemented and robust management pathways are in place, has a positive effect on clinical outcomes. In the past decade, NBS has undergone rapid expansion and an unprecedented number of infants with cystic fibrosis have access to early diagnosis and care. Cystic fibrosis NBS has now moved on from the development phase and is entering an era of consolidation. In the future, research should focus on the rationalisation and optimisation of existing programmes, with particular attention to bioethical implications such as unwanted detection of carriers and inconclusive diagnoses.
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Sweat chloride and Immunoreactive Trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis
Archives of disease in childhood, 2016Co-Authors: Carlo Castellani, Gloria Tridello, Anna Tamanini, Baroukh M. AssaelAbstract:Newborns with raised immunoTrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator (CFTR) mutations of which at least one is not acknowledged to be cystic fibrosis (CF)-causing are at risk of developing clinical manifestations consistent with CFTR-related disorders or even CF. It is not known whether newborns with similar genotypes and normal Immunoreactive Trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007).
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inconclusive diagnosis of cystic fibrosis after newborn screening
Pediatrics, 2015Co-Authors: Carlo Castellani, Chee Y. Ooi, Katherine Keenan, Margaret Boland, Candice L. Bjornson, Julie Avolio, Sonia Volpi, Tom Kovesi, Mark A. ChilversAbstract:OBJECTIVES: To prospectively study infants with an inconclusive diagnosis of cystic fibrosis (CF) identified by newborn screening (NBS; “CF screen positive, inconclusive diagnosis” [CFSPID]) for disease manifestations. METHODS: Infants with CFSPID and CF based on NBS from 8 CF centers were prospectively evaluated and monitored. Genotype, phenotype, repeat sweat test, serum Trypsinogen, and microbiology data were compared between subjects with CF and CFSPID and between subjects with CFSPID who did (CFSPID→CF) and did not (CFSPID→CFSPID) fulfill the criteria for CF during the first 3 years of life. RESULTS: Eighty-two subjects with CFSPID and 80 subjects with CF were enrolled. The ratio of CFSPID to CF ranged from 1:1.4 to 1:2.9 in different centers. CFTR mutation rates did not differ between groups; 96% of subjects with CFSPID and 93% of subjects with CF had 2 mutations. Subjects with CFSPID had significantly lower NBS Immunoreactive Trypsinogen (median [interquartile range]:77 [61–106] vs 144 [105–199] μg/L; P Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated in 12% and 5%, respectively, of subjects with CFSPID. CF was diagnosed in 9 of 82 (11%) subjects with CFSPID (genotype and abnormal sweat chloride = 3; genotype alone = 4; abnormal sweat chloride only = 2). Sweat chloride was abnormal in CFSPID→CF patients at a mean (SD) age of 21.3 (13.8) months. CFSPID→CF patients had significantly higher serial sweat chloride ( P P = .009) levels than did CFSPID→CFSPID patients. CONCLUSIONS: A proportion of infants with CFSPID will be diagnosed with CF within the first 3 years. These findings underscore the need for clinical monitoring, repeat sweat testing at age 2 to 3 years, and extensive genotyping.
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Cystic fibrosis carriers have higher neonatal Immunoreactive Trypsinogen values than non-carriers.
American journal of medical genetics. Part A, 2005Co-Authors: Carlo Castellani, Luigi Picci, Maurizio Scarpa, Maria Cristina Dechecchi, Luisa Zanolla, Baroukh M. Assael, Franco ZacchelloAbstract:Following cystic fibrosis (CF) neonatal screening implementation, a high frequency of heterozygotes has been reported among neonates with elevated Immunoreactive Trypsinogen (IRT) and normal sweat chloride levels. We studied the relationship between normal IRT values and CF heterozygosity: 10,000 neonates were screened for CF by IRT measurement and tested for 40 CF mutations; the 294 carriers detected were coupled with newborns negative to the same genetic testing, and the two groups' IRT levels compared. Heterozygotes had higher IRT levels than their controls (mean 35.32 vs. 27.58 microg/L, P
Anne Marie Comeau - One of the best experts on this subject based on the ideXlab platform.
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Cystic fibrosis newborn screening: using experience to optimize the screening algorithm
Journal of Inherited Metabolic Disease, 2010Co-Authors: Jaime E. Hale, Richard B. Parad, Henry L. Dorkin, Robert Gerstle, Allen Lapey, Brian P. O’sullivan, Terry Spencer, William Yee, Anne Marie ComeauAbstract:Newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early diagnosis and improved outcomes in patients with CF and has been universally available in the state of Massachusetts since 1999 using an Immunoreactive Trypsinogen (IRT)-DNA algorithm. Ideally, CF NBS is incorporated as part of an integrated NBS system that allows for comprehensive and coordinated education, laboratory screening, clinical follow-up, and evaluation so that evidence-based data can be used to maximize quality improvements and optimize the screening algorithm. The New England Newborn Screening Program (NENSP) retrospectively analyzed Massachusetts’s CF newborn screening data that yielded decisions to eliminate a screen-positive category, maintain the IRT cutoff value that prompts the second tier DNA testing, and communicate CF relative risk to primary care providers (PCPs) based on categorization of positive CF NBS results.
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diagnostic dilemmas resulting from the Immunoreactive Trypsinogen dna cystic fibrosis newborn screening algorithm
The Journal of Pediatrics, 2005Co-Authors: Richard B. Parad, Anne Marie ComeauAbstract:Objective To quantitate the proportion of infants identified through cystic fibrosis (CF) newborn screening (NBS) by an Immunoreactive Trypsinogen (IRT)/DNA screening algorithm who have an unclear diagnosis as defined by the findings of an elevated IRT level and either 1) 2 CF gene (CFTR) mutations detected and sweat chloride level Study design Using the 4-year cohort of CF-affected infants recently described by the Massachusetts CF NBS program, we identified and described the number of infants with the diagnostic characteristics (diagnostic dilemmas) aforementioned. Results Of infants with positive results on CF NBS who had 1 CFTR mutation detected and a borderline sweat chloride concentration, nearly 20% displayed a second CFTR mutation on further evaluation. Of all infants with positive CF NBS results considered affected with CF, 11% had a diagnosis that fell into 1 of the diagnostic dilemma categories aforementioned. Conclusions Four problematic diagnostic categories generated by CF NBS are defined. In the absence of data on the natural history of such infants, careful follow-up is recommended for infants in whom a definitive diagnosis is elusive.
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population based newborn screening for genetic disorders when multiple mutation dna testing is incorporated a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections
Pediatrics, 2004Co-Authors: Anne Marie Comeau, Richard B. Parad, Henry L. Dorkin, Allen Lapey, Mark Dovey, Robert S Gerstle, Kenan Haver, Brian Osullivan, David A WaltzAbstract:Objectives. Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated Immunoreactive Trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (ΔF508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders. The objective of this study was to evaluate technical feasibility and practical implications of 2-tiered CF newborn screening that uses testing for multiple mutations (multiple-CFTR-mutation testing). Methods. We implemented statewide CF newborn screening using a 2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT then had multiple-CFTR-mutation testing. Infants who screened positive by detection of 1 or 2 mutations or extremely elevated IRT (>99.8%; failsafe protocol) were then referred for definitive diagnosis by sweat testing. We compared the number of sweat-test referrals using single- with multiple-CFTR-mutation testing. Initial physician assessments and diagnostic outcomes of these screened-positive infants and any affected infants missed by the screen were analyzed. We evaluated compliance with our screening and follow-up protocols. All Massachusetts delivery units, the Newborn Screening Program, pediatric health care providers who evaluate and refer screened-positive infants, and the 5 Massachusetts CF Centers and their affiliated genetic services participated. A 4-year cohort of 323 506 infants who were born in Massachusetts between February 1, 1999, and February 1, 2003, and screened for CF at ∼2 days of age was studied. Results. A total of 110 of 112 CF-affected infants screened (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation screening; 2 false-negative screens did not show elevated IRT. A total of 107 (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation screen, and 3 had positive screens on the basis of the failsafe protocol. In contrast, had we used single-mutation testing, only 96 (87%) of the 110 would have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had positive screens on the basis of the failsafe protocol, and an additional 6 infants would have had false-negative screens. Among 110 CF-affected screened-positive infants, a likely “genetic diagnosis” was made by the multiple-CFTR-mutation screen in 82 (75%) versus 55 (50%) with ΔF508 alone. Increased sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals for sweat testing and carrier identifications than testing with ΔF508 alone. Conclusions. Use of multiple-CFTR-mutation testing improved sensitivity and postscreening prediction of CF at the cost of increased referrals and carrier identification.
Frank J. Accurso - One of the best experts on this subject based on the ideXlab platform.
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evidence for a causal relationship between early exocrine pancreatic disease and cystic fibrosis related diabetes a mendelian randomization study
Diabetes, 2014Co-Authors: David Soave, Frank J. Accurso, Katherine Keenan, Marci K. Sontag, Melissa R Miller, Jiafen Gong, Lei Sun, Johanna M Rommens, Peter R Durie, Lisa J StrugAbstract:Circulating Immunoreactive Trypsinogen (IRT), a biomarker of exocrine pancreatic disease in cystic fibrosis (CF), is elevated in most CF newborns. In those with severe CF transmembrane conductance regulator (CFTR) genotypes, IRT declines rapidly in the first years of life, reflecting progressive pancreatic damage. Consistent with this progression, a less elevated newborn IRT measure would reflect more severe pancreatic disease, including compromised islet compartments, and potentially increased risk of CF-related diabetes (CFRD). We show in two independent CF populations that a lower newborn IRT estimate is associated with higher CFRD risk among individuals with severe CFTR genotypes, and we provide evidence to support a causal relationship. Increased loge(IRT) at birth was associated with decreased CFRD risk in Canadian and Colorado samples (hazard ratio 0.30 [95% CI 0.15–0.61] and 0.39 [0.18–0.81], respectively). Using Mendelian randomization with the SLC26A9 rs7512462 genotype as an instrumental variable since it is known to be associated with IRT birth levels in the CF population, we provide evidence to support a causal contribution of exocrine pancreatic status on CFRD risk. Our findings suggest CFRD risk could be predicted in early life and that maintained ductal fluid flow in the exocrine pancreas could delay the onset of CFRD.
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Genetic and physiologic correlates of longitudinal Immunoreactive Trypsinogen decline in infants with cystic fibrosis identified through newborn screening
The Journal of pediatrics, 2006Co-Authors: Marci K. Sontag, Mary Corey, John E. Hokanson, Julie A. Marshall, Steve S. Sommer, Gary O. Zerbe, Frank J. AccursoAbstract:Objectives To characterize the time course and physiologic significance of decline in serum Immunoreactive Trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability. Study design We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies. Results Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable. Conclusions IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.
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Two-tiered Immunoreactive Trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes.
The Journal of Pediatrics, 2005Co-Authors: Marci K. Sontag, Keith B. Hammond, Julian Zielenski, Jeffrey S Wagener, Frank J. AccursoAbstract:Objective To examine Immunoreactive Trypsinogen (IRT)-based screening for cystic fibrosis (CF) for recall rate, genotype distribution, and “borderline” sweat test results. Study design CF newborn screening in Colorado began in 1982, and >1,153,000 infants were screened through 2002 with an IRT-based screen (IRT/IRT). Results We have identified 313 infants with CF, giving an overall incidence of 1 in 3684 and a Hispanic incidence of 1 in 6495. Fifty-five infants with meconium ileus (17.6%) were excluded from analysis. Fourteen infants with false-negative results were identified (5.4%). The average recall rate was 0.6%, with a positive predictive value of 4.7%. Ninety-three percent of the infants had at least 1 ΔF508 mutation, and 98% of the infants had at least 1 mutation from the American College of Medical Genetics recommended panel. Six infants had hyperTrypsinogenemia and borderline results on sweat tests (30-60 mmol/L). Increased variability in sweat chloride levels were seen in these infants compared with infants with homozygous ΔF508. Three children with initial borderline results on sweat tests had CF diagnosed. Conclusions The recall and false-negative rates of our IRT/IRT CF screening program are reported. Additionally, genotypes of the patients identified mirror the CF population genotypes, reflecting similar disease severity in the screened population. Finally, infants with persistent hyperTrypsinogenemia and borderline sweat test results need long-term follow-up.
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Immunoreactive Trypsinogen levels in infants with cystic fibrosis complicated by meconium ileus
Screening, 1993Co-Authors: Lee S. Rusakow, Steven H. Abman, Ronald J. Sokol, William K. Seltzer, Keith B. Hammond, Frank J. AccursoAbstract:Abstract To examine abnormalities in Immunoreactive Trypsinogen (IRT) in infants with cystic fibrosis (CF) and meconium ileus (MI) and to evaluate the utility of IRT as a diagnostic aid in MI, we compared IRT in 19 infants with CF and MI to values in normal infants and in 91 infants with CF without MI. Infants with CF without MI were identified between 1982–1989 through a statewide screening program based on IRT measurements ( n =83) or through clinical presentation ( n = 8). Infants with MI were identified through clinical presentation during the same period. The IRT level of MI patients as a group (195±23 ng/ml) was greater than the cutoff value for IRT in normal infants (140 ng/ml, corresponding to the 99.7th percentile for infants less than 20 days of age; P P
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efficacy of statewide neonatal screening for cystic fibrosis by assay of Trypsinogen concentrations
The New England Journal of Medicine, 1991Co-Authors: Keith B. Hammond, Steven H. Abman, Ronald J. Sokol, Frank J. AccursoAbstract:Abstract Background. To evaluate the feasibility and efficacy of measuring Immunoreactive Trypsinogen in blood to screen for cystic fibrosis, we performed this test in 279,399 newborns in Colorado from 1982 to 1987. Methods. Immunoreactive Trypsinogen was measured in dried blood spots when the infants were 1 to 4 days old; if the level was elevated (≥140 μg per liter), the measurement was repeated (mean age, 38 days); if the level was again elevated, sweat testing was performed (mean age, 49 days). For the second test, two cutoff levels (120 and 80 μg per liter) were evaluated. Results. We found an incidence of cystic fibrosis of 1 in 3827 (0.26 per 1000), with 3.2 newborns per 1000 requiring repeat measurement. When adjusted for race and compliance with testing, the incidence among the white infants (1 in 2521) was close to the expected incidence. The false positive rate with the initial cutoff level (92.2 percent) was similar to the rate found in neonatal screening programs for other diseases. False neg...
Michel Roussey - One of the best experts on this subject based on the ideXlab platform.
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Combining Immunoreactive Trypsinogen and Pancreatitis-Associated Protein Assays, a Method of Newborn Screening for Cystic Fibrosis that Avoids DNA Analysis
The Journal of Pediatrics, 2005Co-Authors: Jacques Sarles, Patrice Berthezene, Michel Roussey, Christian Le Louarn, Claude Somma, Jean-marc Perini, Michael Catheline, Sophie Mirallié, Karine Luzet, Jean-pierre FarriauxAbstract:Objectives To evaluate the performance of a strategy in which, after Immunoreactive Trypsinogen (IRT) determination, genetic analysis is replaced by a biological test, the pancreatitis-associated protein (PAP) enzyme-linked immunosorbent assay (ELISA). Study design The French newborn screening program includes cystic fibrosis (CF) screening by the IRT/CFTR mutation strategy. PAP was assayed on screening cards, in parallel with IRT, in all newborns from 5 French regions (n = 204,749). Analysis of PAP values in CF and non-CF newborns with elevated IRT allowed direct comparison between the current strategy and the proposed IRT/PAP strategy. Results A protocol in which newborns with IRT >50 ng/mL and PAP >1.8 ng/mL and those with IRT >100 ng/mL and PAP >1.0 ng/mL are directly recalled for sweat testing would have the same performance as the IRT/CFTR mutation strategy. Conclusions The IRT/PAP strategy is an alternative for CF newborn screening, which avoids the drawbacks of genetic analysis and is cheaper and easier to implement than the current IRT/CFTR mutation strategy.
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neonatal screening for cystic fibrosis in brittany france assessment of 10 years experience and impact on prenatal diagnosis
The Lancet, 2000Co-Authors: Virginie Scotet, Michel Roussey, Jean-pierre Codet, P. Parent, G. Rault, M. Dagorne, A. Lemoigne, H. Journel, Marc De Braekeleer, Michael CathelineAbstract:Summary Background Neonatal screening for cystic fibrosis has been a subject of debate over the past few years. This study assesses 10 years of neonatal screening in Brittany, France, and examines its impact on prenatal screening of subsequent pregnancies in couples with an affected child. Methods The study included all the neonates screened for cystic fibrosis in Brittany from Jan 1, 1989, to Dec 31, 1998. The screening consisted of an Immunoreactive Trypsinogen assay from dried blood spots, plus, from 1993, mutation analysis. Data were collected on incidence of cystic fibrosis, and genotypic and biochemical characteristics. The use of prenatal screening of subsequent pregnancies in affected families was also investigated. Findings Of the 343 756 neonates screened, 118 children with cystic fibrosis were identified, giving an incidence of one in 2913. All mutated alleles were characterised: 34 different mutations resulting in 36 genotypes were detected. The introduction of DNA analysis into the protocol greatly reduced the recall rate and increased the sensitivity of the test. The mean cost of the screening programme was US$2·32 per screened child. 39 (34%) of the families identified by neonatal screening opted for subsequent prenatal diagnosis at least once. 12 couples would have benefited from this procedure while their first child was still symptom-free. 42 healthy children were born, and 18 pregnancies were terminated (therapeutic abortion rate of 100%). Interpretation We have shown the feasibility of neonatal screening for cystic fibrosis in Brittany. Through the detection of a large range of mutations, neonatal screening provides the opportunity for more reliable prenatal diagnosis and cascade screening. The neonatal screening programme described here could provide a good model for other countries intending to initiate such a scheme.
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Blood concentrations of pancreatitis associated protein in neonates: relevance to neonatal screening for cystic fibrosis
Archives of Disease in Childhood - Fetal and Neonatal Edition, 1999Co-Authors: Jacques Sarles, Juan L. Iovanna, S. Barthellemy, Michel Roussey, Claude Férec, Jean-pierre Farriaux, Annick Toutain, Jacques Berthelot, Nicole Maurin, Jean-pierre CodetAbstract:AIM To determine whether pancreatitis associated protein (PAP) is a marker for cystic fibrosis which could be used in neonatal screening for the disease. METHODS PAP was assayed on screening cards from 202 807 neonates. Babies with PAP ⩾ 15 ng/ml, or ⩾ 11.5 ng/ml and Immunoreactive Trypsinogen (IRT) ⩾ 700 ng/ml were recalled for clinical examination, sweat testing, and cystic fibrosis transmembrane regulator (CFTR) gene analysis. RESULTS Median PAP value was 2.8 ng/ml. Forty four cases of cystic fibrosis were recorded. Recalled neonates (n=398) included only 11 carriers. A receiver operating characteristic curve analysis showed that PAP above 8.0 ng/ml would select 0.76% of babies, including all those with cystic fibrosis, except for one with meconium ileus and two with mild CFTR mutations. Screening 27 146 babies with both PAP and IRT showed that only 0.12% had PAP > 8.0 ng/ml and IRT > 700 ng/ml, including all cases of cystic fibrosis. CONCLUSION PAP is increased in most neonates with cystic fibrosis and could be used for CF screening. Its combination with IRT looks promising. Key messages CF neonatal screening with PAP is technically feasible in the same environment as other neonatal screenings (PKU, hypothyroidism) CF neonatal screening with PAP alone performs similarly to screening with IRT alone, with less carrier detection Combining PAP with IRT for CF neonatal screening could be as efficient as the IRT/DNA strategy, but would be cheaper and incur limited carrier detection If a legal requirement for informed consent before DNA testing has expired, the PAP/IRT strategy would be an alternative to the IRT/DNA strategy
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Neonatal screening for cystic fibrosis: result of a pilot study using both Immunoreactive Trypsinogen and cystic fibrosis gene mutation analyses
Human Genetics, 1995Co-Authors: Claude Férec, Jean-pierre Codet, C. Verlingue, P. Parent, J. F. Morin, G. Rault, M. Dagorne, A. Lemoigne, H. Journel, Michel RousseyAbstract:We have evaluated a two-tier neonatal cystic fibrosis (CF) screening of Immunoreactive Trypsinogen (IRT) followed by CFTR gene mutation analysis using a systematic scanning of exons 7, 10, and 11, and, if necessary, by direct DNA sequencing. Over an 18-month period we screened 32,300 neonates born in the western part of Britanny. The first tier, involving IRT screening at 3 days of age, utilizes a low elevation of the Trypsinogen level (600 ng/ml), which is highly sensitive. The second tier, which corresponds to the exhaustive screening for mutations in three exons of the gene, is highly specific for this population (Britanny). The false positive rate is very low, and no false negatives have been reported to date. This strategy has allowed the identification of five novel alleles (V322A, V317A, 1806 del A, R553G, G544S). Moreover the test can be adapted to other countries in which the distribution of mutations is established.
