CFTR-related Metabolic Syndrome Research Articles

New York cystic fibrosis consortium newborn screening quality improvement: Development and implementation of a statewide consensus recommendations for management of infants with CFTR-related metabolic syndrome.

New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium. Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies. Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire. With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS.

334 Expanding the role of mental health providers within CFTR-related metabolic syndrome care: Descriptive report and considerations from a cystic fibrosis center

334 Expanding the role of mental health providers within CFTR-related metabolic syndrome care: Descriptive report and considerations from a cystic fibrosis center

CFTR-Related Metabolic Syndrome: Genetic Variants Increasing Pancreatitis Risk in the Pediatric Puerto Rican Population

CFTR-related metabolic syndrome (CRMS) is a novel diagnosis due to widespread use of and advances in the newborn screening (NBS) process for cystic fibrosis (CF) in the United States of America, allowing for the diagnosis of asymptomatic children with CF. Before 2015, a large Puerto Rican pediatric population was not screened for CF in the NBS test. Studies have shown that patients presenting with idiopathic recurrent or chronic pancreatitis have an increased frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We present a retrospective chart review of 12 pediatric cases (n = 12) that were presented to an outpatient community clinic with clinical manifestations associated with CF. The pancreatic insufficiency prevalence (PIP) score was calculated on CFTR mutations. The mutations considered for the calculation of the PIP score were: F508del (c.1521_1523del), V201M (c.601G > A), I507del (c.1519_1521del), and L1335P (c.4004T > C). V201M mutation was classified as mild in both PIP scores, and a correlation with pancreatitis was noted. Clinical manifestations vary in cases with the V201M variant (c.601G > A). One case was diagnosed with CFTR-related disorder (CRD) and recurrent pancreatitis. It is important to consider CRMS or CRD as a differential diagnosis in the pediatric population of Puerto Rico due to the implications and increased risk of pancreatitis and other CF-related complications.

Immunoreactive Trypsinogen Levels in Infants Born to Women with Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor

Background/Objective:Cystic Fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene affecting people of every race and ethnicity in the US. Highly effective modulator therapies (HEMT), such as elexacaftor-tezacaftor-ivacaftor (ETI), correct misfolding and/or improve functioning of the abnormal CFTR protein to lessen disease severity. Most people with CF are diagnosed following abnormal newborn screening (NBS), which involves measuring levels of immunoreactive trypsinogen (IRT). There have been case reports of falsely low IRT levels among infants with CF exposed to ETI in utero, but an overall assessment of IRT levels among these infants has not been conducted. We hypothesize that infants born to mothers with CF taking ETI (ETI-exposed) may have lower IRT levels than newborns with CF, CFTR-related metabolic syndrome (CRMS), or CF carriers.Methods:NBS data from infants born between 2020-22 in Indiana with at least one CFTR mutation were collected and compared to infants born to mothers with CF taking ETI followed at Indiana University, regardless of CFTR mutation status. Infants were categorized as: CF, CRMS, Carrier, ETI-exposed, and Unknown (i.e., diagnosis not determined). An ANOVA test was performed on log-transformed data, with p-values adjusted for Dunnett’s to compare IRT levels of infant groups to ETI-exposed group.Results:There were 51 children with CF, 21 with CRMS, 489 CF carriers, and 19 ETI-exposed infants. Compared to other groups, ETI-exposed infants had a lower median IRT value and IQR (p<0.0001). To our knowledge, there are no CF diagnoses among ETI-exposed infants.Conclusion:IRT levels for ETI-exposed infants, who are obligate CF carriers, were lower than for other infants with CF-related diagnoses, raising the likelihood of false normal NBS results. ETI-exposed infants should have CFTR mutation analysis performed to correctly categorize them as CF, CRMS, or CF carriers.

Parental Preferences about Policy Options Regarding Disclosure of Incidental Genetic Findings in Newborn Screening: Using Videos and the Internet to Educate and Obtain Input.

Our objective was to develop and test a new approach to obtaining parental policy guidance about disclosure of incidental findings of newborn screening for cystic fibrosis (CF), including heterozygote carrier status and the conditions known as CFTR-related metabolic syndrome (CRMS) and/or cystic fibrosis screen positive inconclusive diagnosis, CFSPID. The participants were parents of infants up to 6 months old recruited from maternity hospitals/clinics, parent education classes and stores selling baby products. Data were collected using an anonymous, one-time Internet-based survey. The survey introduced two scenarios using novel, animated videos. Parents were asked to rank three potential disclosure policies—Fully Informed, Parents Decide, and Withholding Information. Regarding disclosure of information about Mild X (analogous to CRMS/CFSPID), 57% of respondents ranked Parents Decide as their top choice, while another 41% ranked the Fully Informed policy first. Similarly, when considering disclosure of information about Disease X (CF) carrier status, 50% and 43% gave top rankings to the Fully Informed and Parents Decide policies, respectively. Less than 8% ranked the Withholding Information policy first in either scenario. Data from value comparisons suggested that parents believed knowing everything was very important even if they became distressed. Likewise, parents preferred autonomy even if they became distressed. However, when there might not be enough time to learn everything, parents showed a slight preference for deferring decision-making. Because most parents strongly preferred the policies of full disclosure or making the decision, rather than the withholding option for NBS results, these results can inform disclosure policies in NBS programs, especially as next-generation sequencing increases incidental findings.

Impact of Pancreatitis-Associated Protein on Newborn Screening Outcomes and Detection of CFTR-Related Metabolic Syndrome (CRMS)/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A Monocentric Prospective Pilot Experience.

Pancreatitis-Associated Protein (PAP)-based Cystic Fibrosis (CF) newborn bloodspot screening (NBS) protocols detect less CFTR-Related Metabolic Syndrome (CRMS)/CF Screen Positive, Inconclusive Diagnosis (CFSPID). We prospectively evaluated the impact of PAP as the second step of the CF NBS protocol, before the CFTR genetic analysis, on NBS outcomes and CRMS/CFSPID detection in the Tuscany region, Italy. In parallel to the usual protocol (IRT/DNA, protocol 1), PAP was analyzed in IRT-positive infants (IRT/PAP/DNA, protocol 2) from 1 June 2020 until 31 May 2022. We defined an infant as NBS positive if PAP was >1.8 μg/L for IRT value 99th percentile-100 μg/L or >0.6 μg/L for IRT value >100 μg/L. To increase the positive predictive value (PPV) of protocol 2, we retrospectively lowered the upper IRT range value from 100 to 90 μg/L (modified protocol 2). We identified 8 CF and 13 CRMS/CFSPID with protocol 1, 5 CF and 5 CRMS/CFSPID with protocol 2 and 8 CF and 5 CRMS/CFSPID with modified protocol 2. With the PAP-based protocols, we observed a reduction of sweat tests, healthy carrier detection and a significant increase in PPV to 15.38%. Further data are needed in order to evaluate the outcomes of CRMS/CFSPID after a long follow-up.

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

This article uses cystic fibrosis as a case study to examine how physicians and scientists have navigated uncertainty following newborn screening. Despite the many benefits of newborn screening, including earlier diagnosis, therapeutic intervention, and a reduced diagnostic odyssey, this public health approach also comes with challenges. For example, physicians began to document infants with indeterminate diagnoses - those with a positive screen who did not clearly fit into the cystic fibrosis or “normal” categories - by the early twenty first century. As a means of addressing this uncertainty and to facilitate long-term follow up of such infants, the U.S. Cystic Fibrosis Foundation recommended in 2009 that a new diagnostic term, CFTR-related metabolic syndrome (CRMS), be used. However, the CRMS label was not favored in Europe and a different term, cystic fibrosis screen positive, inconclusive diagnosis (CFSPID), was adopted in 2015 instead. Efforts to address the uncertainty associated with indeterminate diagnoses have been complicated, as stakeholders have held differing views about whether the screening algorithms should aim to maximize or minimize CRMS/CFSPID cases. Many who favor the identification of babies with CRMS/CFSPID note that they are at increased risk of developing symptoms and signs consistent with a cystic fibrosis diagnosis. In contrast, those who support algorithms that reduce CRMS/CFSPID cases point to iatrogenic harms associated with the medicalization of children who may remain healthy into adulthood. Furthermore, investigators have grappled with how best to ensure equity in newborn screening among different racialized groups while concomitantly attempting to minimize false positive results. These issues are applicable beyond the context of cystic fibrosis, especially as programs contemplate the incorporation or expanded use of next generation sequencing in algorithms for a wide range of diseases, and this history highlights how efforts to reduce uncertainty in one setting can lead to new and persistent sources of uncertainty in other areas.

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

THE CF QUANTUM SWEAT TEST: NOT READY FOR CLINICAL USE

The CF Quantum Test (CFQT) showed promise in a previous pilot study, however there was greater imprecision in one patch lot. Following the pilot study, the manufacturer changed their fabricating procedures. Subjects with previously diagnosed CF or subjects who required a sweat test for clinical reasons were invited to undergo the CFQT research test and a conventional sweat test (Macroduct®; collection and chloride analysis via the ChloroChek®; chloridometer). Previously diagnosed CF (n= 41) and CRMS (CFTR-related metabolic syndrome)/CFSPID (cystic fibrosis screen positive inconclusive diagnosis) (n= 3) patients and patients who required a sweat test for clinical indications (n=22) were recruited to have bilateral CFQT along with the Macroduct®; test performed on the same day. Pairs of data from each test were plotted as a correlation graph, bias plot and Bland Altman plot. Coefficient of variation (CV) between extremities and QNS rates for both tests were calculated. The CV between left and right extremities was greater in the CFQT (9.5%) compared to the Macroduct®; (4.8%). The QNS (quantity not sufficient) rates of the two tests were comparable (CFQT: 6.8%; Macroduct®;: 6.0%). There was greater imprecision with the CFQT results. The diagnostic agreement between the two tests was 100% positive percent agreement (95% CI: 90–100%), 100% negative percent agreement (95% CI: 80–100%), 67% intermediate percent agreement (95% CI: 30%–80%), and 92% overall percent agreement (95% CI: 80–100%). This follow-up study demonstrated that the CFQT is not analytically nor diagnostically reliable. (Clinicaltrials.gov identifier NCT01345617)

Cystic Fibrosis Diagnosis in Newborns, Children, and Adults.

The diagnosis of cystic fibrosis (CF) has traditionally relied on the presence of clinical features of the disease. Today, diagnosis through newborn screening (NBS) is becoming the standard of modern CF care. CF NBS programs can identify CF prior to clinical presentation, but for the advantages of an early diagnosis to accrue a scrupulous system must be in place to ensure all steps in the program are performing. As we move rapidly into the era of CF transmembrane conductance regulator (CFTR) protein modulators, the opportunity to start a presymptomatic infant, identified through CF NBS, on these agents offers the prospect of true disease-modifying interventions which could result in a paradigm shift in CF care.Conversely, the introduction of NBS has resulted in many children being asymptomatic at the time of diagnosis. Some screened newborns are classified as "CF Screening Positive, Inconclusive Diagnosis", or "CFTR-related metabolic syndrome" when the diagnosis can neither be confirmed nor excluded. Appropriate assessment and follow-up should be arranged at specialist centers as a proportion of these infants and adults will eventually be diagnosed with CF.Symptoms and signs are particularly pertinent when considering a diagnosis of CF outside the context of NBS. In older patients with a late diagnosis, the spectrum of clinical presentation can be very variable with vigilant clinicians from multiple specialties suspecting the diagnosis in conditions such as recurrent pulmonary infections, male infertility, pancreatitis, nasal polyposis, and malabsorption.In addition to clinical symptoms or positive NBS results, sweat test and genetic analysis are cornerstones in the diagnosis of CF, but in some cases the diagnosis cannot be confirmed on genetic or sweat testing. Difficult diagnosis may be supported by in vivo or ex vivo electrophysiology measurements on respiratory or intestinal epithelia. This can be done by either measuring transepithelial nasal potential difference or intestinal current measurements.

Image-based β-adrenergic sweat rate assay captures minimal cystic fibrosis transmembrane conductance regulator function.

Background:There is a need to prognosticate the severity of cystic fibrosis (CF) detected by newborn screening (NBS) by early assessment of CF Transmembrane Conductance Regulator protein function (CFTR). We introduce novel instrumentation and protocol for evaluating CFTR activity as reflected by β-adrenergically stimulated sweat secretion.Methods:A pixilated Image-Sensor detects sweat rates. Compounds necessary for maximum sweat gland stimulation are applied by Iontophoresis, replacing intradermal injections. Results are compared to a validated β-adrenergic assay that measures sweat secretion by evaporation (Evaporimetry).Results:Ten healthy controls (HC), 6 Heterozygous (Carriers), 5 with cystic fibrosis screen positive, inconclusive diagnosis (CFSPID), and 12 cystic fibrosis (CF) individuals completed testing. All individuals with minimal and residual function CFTR mutations had low ratios of β-adrenergically stimulated sweat rate to cholinergically stimulated sweat rate (β/chol) as measured by either assay.Conclusions:β adrenergic assays quantitate CFTR dysfunction in the secretory pathway of sweat glands in CF and CRMS/CFSPID populations. This novel Image-Sensor and Iontophoresis protocol detect CFTR function with minimal and residual function and is a feasible test for young children because it is insensible to movement and it decreases the number of injections. It may also assist to distinguish between CF and CRMS/CFSPID diagnosis.

Revisiting sweat chloride test results based on recent guidelines for diagnosis of cystic fibrosis

ObjectivesRecent sweat chloride guidelines published by the Cystic Fibrosis Foundation changed the intermediate sweat chloride concentration range from 40–59 mmol/L to 30–59 mmol/L for age > 6 months. We wanted to know how this new guideline would impact detection of cystic fibrosis among patients who previously had sweat tests done at Texas Children's Hospital. MethodsWe revisited sweat chloride test results (n = 3012) in the last 5 years at Texas Children's Hospital based on the new guidelines on diagnosis of cystic fibrosis from the Cystic Fibrosis Foundation. ResultsWe identified 125 that would be reclassified in the intermediate sweat chloride value with the new guidelines that were classified as “unlikely to have CF” in the previous guidelines. 8 (32%) patients with CFTR gene testing were positive for CFTR gene mutation(s). 4 (50%) of these patients were identified to have 2 CFTR mutations. One had variant combination that was reported to cause CF but all were diagnosed with CFTR-related metabolic syndrome. ConclusionOur findings concur with the new CF diagnosis guidelines that changing the intermediate cut-off to 30–59 mmol/L sweat chloride concentration in combination with CFTR genetic analysis enhances the probability of identifying individuals that have risk of developing CF or have CF and enables for earlier therapeutic intervention.

P289 A case of Phosphoacetylglucosamine Mutase (PGM3) deficiency in a patient with CFTR-related metabolic syndrome (CRMS)

P289 A case of Phosphoacetylglucosamine Mutase (PGM3) deficiency in a patient with CFTR-related metabolic syndrome (CRMS)

Low Beta-Adrenergic Sweat Responses in Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome Children.

β-adrenergically stimulated sweat secretion depends on the function of the cystic fibrosis transmembrane conductance regulator (CFTR) and discriminates between cystic fibrosis (CF) patients and healthy controls. Therefore, we sought to determine the feasibility, safety, and efficacy of assaying β-adrenergic sweating in children identified by CF newborn screening to help determine prognoses for individuals with CFTR-related metabolic syndrome (CRMS). Preschool age children with a positive newborn screening test for CF participated in this cross-sectional study. Sweat rates were measured by evaporimetery (cyberDERM, inc.) as transepidermal water losses (g H2O/m2/h) before and after selectively stimulating sweat glands either cholinergically or β-adrenergically. Net peak sweat responses assayed as evaporation rates were compared between CF and CRMS cohorts. After a pilot test in adults, children between 4 and 6 years of age were evaluated (CF, n = 16; CRMS, n = 10). The test protocol was well tolerated; electrocardiograms and vital signs were within normal range for all subjects. The mean evaporative sweat rates in both groups in response to cholinergic stimulation were similar (CF, 60.3 ± 23.8; CRMS, 57.7 ± 13.9; p = 0.72) as well as to β-adrenergic stimulation (CF, 1.1 ± 1.7; CRMS, 2.0 ± 2.0; p = 0.14). The β-adrenergic sweat test is safe and well tolerated by young children. However, the β-adrenergic sweat secretion rates as measured by evaporimetery did not discriminate between CF and CRMS cohorts.

Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation

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. 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. 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. 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.

Novel insights into the diagnostic and therapeutic challenges of the CFTR metabolic syndrome/CF screen positive indeterminate diagnosis

The growth of cystic fibrosis newborn screening (CF NBS) has led to an increased number of infants with a positive NBS test but inconclusive CF diagnostic testing. In the USA this condition is called CFTR related metabolic syndrome (CRMS), while in Europe the term CF screen positive, inconclusive diagnosis (CFSPID) is used. Recent advances in CF genetics and epidemiologic studies of CRMS/CFSPID have provided new insights into the prevalence and outcomes associated with this condition. Pediatr Pulmonol. 2016;51:S45-S48. © 2016 Wiley Periodicals, Inc.

Improving the Sensitivity and Positive Predictive Value in a Cystic Fibrosis Newborn Screening Program Using a Repeat Immunoreactive Trypsinogen and Genetic Analysis

To evaluate the performance of a new cystic fibrosis (CF) newborn screening algorithm, comprised of immunoreactive trypsinogen (IRT) in first (24-48hours of life) and second (7-14days of life) dried blood spot plus DNA on second dried blood spot, over existing algorithms. A retrospective review of the IRT/IRT/DNA algorithm implemented in Colorado, Wyoming, and Texas. A total of 1 520 079 newborns were screened, 32 557 (2.1%) had abnormal first IRT; 8794 (0.54%) on second. Furthermore, 14 653 mutation analyses were performed; 1391 newborns were referred for diagnostic testing; 274 newborns were diagnosed; and 201/274 (73%) of newborns had 2 mutations on the newborn screening CFTR panel. Sensitivity was 96.2%, compared with sensitivity of 76.1% observed with IRT/IRT (105ng/mL cut-offs, P<.0001). The ratio of newborns with CF to heterozygote carriers was 1:2.5, and newborns with CF to newborns with CFTR-related metabolic syndrome was 10.8:1. The overall positive predictive value was 20%. The median age of diagnosis was 28, 30, and 39.5days in the 3 states. IRT/IRT/DNA is more sensitive than IRT/IRT because of lower cut-offs (∼97 percentile or 60ng/mL); higher cut-offs in IRT/IRT programs (>99 percentile, 105ng/mL) would not achieve sufficient sensitivity. Carrier identification and identification of newborns with CFTR-related metabolic syndrome is less common in IRT/IRT/DNA compared with IRT/DNA. The time to diagnosis is nominally longer, but diagnosis can be achieved in the neonatal period and opportunities to further improve timeliness have been enacted. IRT/IRT/DNA algorithm should be considered by programs with 2 routine screens.

Refining the continuum of CFTR-associated disorders in the era of newborn screening.

Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment.

Newborn Screening for Cystic Fibrosis in California.

This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California. From July 16, 2007, to June 30, 2012, a total of 2,573,293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values ≥62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with ≥2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling. Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test-positive infants, respectively). The 3-step model had high detection and low false-positive levels in this diverse population.

Utility of a very high IRT/No mutation referral category in cystic fibrosis newborn screening.

Newborn screening for Cystic Fibrosis (CF) began in New York in October, 2002 using immunoreactive trypsinogen (IRT)/DNA methodology. Infants with at least one CFTR mutation or very high IRT and no mutations (VHIRT) are referred for sweat testing. In a preliminary analysis, we noted a very low positive predictive value (PPV) and preponderance of Hispanic infants in the group of infants with CF referred for VHIRT, which led to a decision to revise, but not eliminate, the VHIRT category. Automatic referral for specimens with VHIRT collected on the day of birth was eliminated, and the VHIRT threshold was raised from 0.2% to 0.1%. In this report, we describe outcomes from VHIRT referrals among 2.4 million infants screened between March 2003 and February 2013. Following the algorithm change, referrals decreased by 37.8% overall (annual mean 1,485 vs. 923), and the VHIRT PPV improved (0.6-1.0%). The number of infants diagnosed has remained consistent at 1 in 4,400 births. The proportion of Black/Hispanic/Asian/Other infants with confirmed CF, CFTR-related metabolic syndrome (CRMS), or possible CF/CRMS was 21.3% in infants with 1-2 mutations, but 75.8% in the VHIRT group. In conclusion, although the PPV among VHIRT referrals remains low, had this category never been implemented, 24 infants with confirmed CF, and 9 infants with CRMS or possible CF/CRMS, most of whom were Hispanic, would have been missed over the 10 years. Information from this study may be helpful in assessing the need for the VHIRT category and algorithm changes in other screening programs.