We believe that the data in this letter clearly demonstrate that even with CFTR2 expansion to 719 variants, striving to achieve equity of early diagnosis of CF via screening requires states to perform a sweat test in all infants with a high IRT level and one identified CFTR variant. This recommended policy can be debated but sweat testing overload should not be the argued as the barrier and CF specialists need to recognize that CFTR2 may never include all of the very rare, “private” pathogenic variants nor will next generation sequencing cover the structural variants such as deletions and duplications.

Rationale: Cystic Fibrosis (CF) newborn screening (NBS) algorithms in the USA vary by state. Differences in CF NBS algorithms could potentially affect the detection rate of CF newborns and lead to disparities in CF diagnosis amongst different racial and ethnic groups. Objectives: Generate a database of CF NBS algorithms in the USA and identify processes that may potentially lead to missed diagnoses or lead to health care disparities. Methods: We sent an online survey to state and regional CF and NBS leaders about the type and threshold of immunoreactive trypsinogen (IRT) cutoff used and methods used for CFTR gene variant analysis. Follow-up by email and phone was done to ensure a response from every state, clarify responses, and resolve discordances . Results: There was wide variation in the NBS algorithms employed by different states. Approximately half the states use a floating IRT cutoff and half use a fixed IRT cutoff. CFTR variant analysis also varied widely, with 2 states analyzing only for the F508del variant and 4 states incorporating CFTR gene sequencing. The other states used CFTR variant panels ranging from 23 to 365 CFTR variants. Conclusions: CF NBS algorithms vary widely amongst the different states in the USA, which affects the ability of CF NBS to diagnose newborn infants with CF consistently and uniformly across the country and potentially may miss more infants with CF from minority populations. Our results identify an important area for quality improvement in CF NBS.

Background: Newborn screening (NBS) for cystic fibrosis (CF) has been underway universally in the USA 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 determinations alone have been transformed to a 2-tier strategy with DNA analyses. Objective: To apply next generation sequencing (NGS) as a method for expanding the DNA tier for identifying variants in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene with minimization of unintended outcomes. Design: Sequential quality improvement project in three phases using plan coupled to statewide follow up and analysis of screening outcomes in comparison to other NBS programs that use CFTR sequencing. 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 cystic fibrosis metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). This led us to a third phase of quality 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 either carriers or CRMS/CFSPID cases.

Introduction: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis generating study was designed to form the basis of additional research and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS. Methods: We included participants in the CF Foundation Patient Registry born 2010-2018 with age at first CF event (first sweat test, clinic visit or hospitalization) by age 365 days. We assessed age of center-reported diagnosis, age at first CF event, demographics and outcomes for three consecutive 3-year cohorts born in 2010-2012, 2013-2015, and 2016-2018. Results: In 6354 infants, median age at diagnosis was earlier than median age at first CF event, which decreased from 1st cohort to 3rd cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was > 0 but height-for-age (HFA) z-score was < 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection rates decreased over time. About 1/3 of infants were hospitalized in the first year of life across cohorts. Conclusion: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts but improving nutritional deficits and reducing infant hospitalizations remain targets for improvement.