BACKGROUND:Among people with cystic fibrosis (CF), limited data exists describing how area-level socioeconomic factors influence in-hospital, emergency room, and ambulatory surgery healthcare utilization. Using the Childhood Opportunity Index (COI) as an area-level composite measure, we aimed to describe the healthcare utilization patterns among children with CF (CwCF) by COI and determine if COI is associated with increased healthcare utilization. METHODS:Retrospective cohort study that utilized the CF Foundation Patient Registry-Pediatric Health Information System dataset. The COI version 3.0 was used. Primary study outcomes included the number of hospital encounters (hospitalizations, emergency room visits, and ambulatory surgeries) between 2009-2022, compared among five COI quintiles. Generalized estimating equations were used to regress hospital encounter on COI quintile with a Poisson distribution and clustered on hospital. RESULTS:8177 CwCF <22 years contributed 65,038 hospital encounters for analysis. Compared to the very high quintile, CwCF in the very low, low, and moderate quintiles had a higher hospitalization risk (very low Relative Risk (RR) 1.31, 95% Confidence Interval (CI) 1.17-1.47; p < 0.001, low RR 1.16, 95%CI 1.04-1.30; p = 0.008, and moderate RR 1.15, 95%CI 1.05-1.25; p = 0.001). In addition, CwCF in the very low group had a higher respiratory-related hospitalization risk (RR 1.60, 95%CI 1.30-1.90; p < 0.01). CONCLUSIONS:CwCF in the lower COI quintiles had a higher hospitalization risk. Future research should focus on underlying area-level drivers of hospitalizations to reduce inpatient utilization.

Rationale: Chronic Pseudomonas aeruginosa (Pa) airway infection is common and a key contributor to diminished lung function and early mortality in persons with cystic fibrosis (PwCF). Risk factors for chronic Pa among PwCF include CFTR (cystic fibrosis transmembrane conductance regulator) genotype, genetic modifiers, and environmental factors. Intensive antibiotic therapy and highly effective modulators do not eradicate Pa in most adolescents and adults with cystic fibrosis. Objectives: To identify new genetic modifiers contributing to the pathophysiology of chronic Pa infection in PwCF. Methods: A total of 4,945 participants in the CF Genome Project with whole-genome sequencing linked to longitudinal clinical data from the 2017 Cystic Fibrosis Foundation Patient Registry were used to conduct a time-to-event genome-wide association study using two definitions of chronic Pa infection. Results: We identified a genome-wide significant association (P = 2.2 × 10-8) between delayed onset of chronic Pa infection and rs194810, a common variant near the gene CHP2, which encodes calcineurin B homolog protein 2 (minor A allele frequency 43%). Survival curves by rs198410 allele dosage show that PwCF homozygous for the A allele are an average of 3 years older when achieving chronic Pa infection compared with G allele homozygotes. Conclusions: Variants near CHP2 are associated with a significant delay in the age of chronic Pa infection among PwCF.

Rationale: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly with 30-50% associated mortality. There is greater mortality and morbidity in infants with CDH-associated pulmonary hypertension (CDH-PH) compared to those without. The natural history of how pulmonary vascular disease in CDH changes with age is not well described. We hypothesize that infants with CDH treated PH (compared to infants with CDH without PH treatment) will have increased disease severity, hospital length of stay, and long-term cardiopulmonary, gastrointestinal, and neurologic complications. Methods: This single center, retrospective cohort study included all children with CDH repaired at Seattle Children's Hospital between January 2014 and April 2022 who received at least 1 pulmonary outpatient visit in the first two years of life. CDH-PH was defined as requiring PH medical therapy during their initial hospitalization, including treprostinil, sildenafil, and/or bosentan. Exclusion criteria included children with CDH who died prior to discharge and children with CDH with complex congenital heart disease. Demographic and clinical characteristics of the two groups during at time of CDH repair were summarized descriptively, and clinical outcomes were compared using Fisher's exact test or Mann-Whitney U test between children with and without PH treatment. Results: Eighty-three children with CDH met criteria for inclusion, and 11 (13%) had CDH-PH (Table 1). The CDH-PH group were more likely to have patch repair (100% for CDH-PH vs 46% for CDH without PH, p=0.001), and were more likely to have an intrathoracic liver (82% for CDH-PH vs 46% for CDH without PH, p=0.048). The CDH-PH group was more likely to receive inhaled nitric oxide (82% vs 26%, p=0.001), require ECMO (55% vs 6%, p <0.001), and require longer duration of mechanical ventilation (36 vs 10 days, p <0.001). Children with CDH-PH had a longer median length of stay of 112 days versus 52 days (p <0.001) and were more likely to be discharged home on diuretics (36% vs 11%, p=0.049). There was no significant difference in the percentage of children discharged home on respiratory support or tube feeds between the two groups. Conclusions: The CDH-PH group is a sicker cohort as evidenced by all requiring patch repair (e.g larger hernia defects), greater utilization of ECMO, and mechanical ventilation These children required a significantly longer hospital stay. The comparison of post-discharge clinical outcomes and complications between children with CDH-PH and CDH without PH treatment will be presented at the ATS conference.

Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

BackgroundCystic fibrosis (CF) is caused by deleterious variants in each CFTR gene. We investigated the utility of whole-gene CFTR sequencing when fewer than two pathogenic or likely pathogenic (P/LP) variants were detected by conventional testing (sequencing of exons and flanking introns) of CFTR.MethodsIndividuals with features of CF and a CF-diagnostic sweat chloride concentration with zero or one P/LP variants identified by conventional testing enrolled in the CF Mutation Analysis Program (MAP) underwent whole-gene CFTR sequencing. Replication was performed on individuals enrolled in the CF Genome Project (CFGP), followed by phenotype review and interrogation of other genes.ResultsWhole-gene sequencing identified a second P/LP variant in 20/43 MAP enrollees (47 %) and 10/22 CFGP enrollees (45 %) who had one P/LP variant after conventional testing. No P/LP variants were detected when conventional testing was negative (MAP: n = 43; CFGP: n = 13). Genome-wide analysis was unable to find an alternative etiology in CFGP participants with fewer than two P/LP CFTR variants and CF could not be confirmed in 91 % following phenotype re-review.ConclusionsWhole-gene CFTR analysis is beneficial in individuals with one previously-identified P/LP variant and a CF-diagnostic sweat chloride. Negative conventional CFTR testing indicates that the phenotype should be re-evaluated.

Rationale: Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). Objectives: We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods: SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run-in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY and a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth, and percent predicted forced expiratory volume in 1 second (ppFEV1) at study entry. Results: Forty-three participants discontinued both therapies by the end of SIMPLIFY, and 63 remained on both, with overall average ppFEV1 of 96.7% at study entry and 3.9 months as the average duration of follow-up from beginning of the first trial to completion of the second trial, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued and those who remained on both therapies (difference: 0.22% off-on; 95% confidence interval = -1.60, 2.03). Changes in lung clearance index at 2.5% starting concentration, patient-reported outcomes, and safety outcomes were also comparable. Patient-reported treatment burden, as measured by a Cystic Fibrosis Questionnaire-Revised subscale, significantly decreased in those who discontinued both therapies. Conclusions: SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared with those who remained on both therapies. These data continue to inform a new era of postmodulator care of people with cystic fibrosis.

Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed markers from the same cohort and outperforms Rsq as a QC metric. In this work, we extended the original MagicalRsq to allow cross-cohort model training and named the new model MagicalRsq-X. We removed the cohort-specific estimated minor allele frequency and included linkage disequilibrium scores and recombination rates as additional features. Leveraging whole-genome sequencing data from TOPMed, specifically participants in the BioMe, JHS, WHI, and MESA studies, we performed comprehensive cross-cohort evaluations for predominantly European and African ancestral individuals based on their inferred global ancestry with the 1000 Genomes and Human Genome Diversity Project data as reference. Our results suggest MagicalRsq-X outperforms Rsq in almost every setting, with 7.3%-14.4% improvement in squared Pearson correlation with true R2, corresponding to 85-218 K variant gains. We further developed a metric to quantify the genetic distances of a target cohort relative to a reference cohort and showed that such metric largely explained the performance of MagicalRsq-X models. Finally, we found MagicalRsq-X saved up to 53 known genome-wide significant variants in one of the largest blood cell trait GWASs that would be missed using the original Rsq for QC. In conclusion, MagicalRsq-X shows superiority for post-imputation QC and benefits genetic studies by distinguishing well and poorly imputed lower-frequency variants.

BACKGROUND AND AIMS:It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. APPROACH AND RESULTS:Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 )] relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes [ CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 )] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies. CONCLUSION:These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.

To identify modifier loci underlying variation in body mass index (BMI) in persons with cystic fibrosis (pwCF), we performed a genome-wide association study (GWAS). Utilizing longitudinal height and weight data, along with demographic information and covariates from 4,393 pwCF, we calculated AvgBMIz representing the average of per-quarter BMI Z scores. The GWAS incorporated 9.8M single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) > 0.005 extracted from whole-genome sequencing (WGS) of each study subject. We observed genome-wide significant association with a variant in FTO (FaT mass and Obesity-associated gene; rs28567725; p value = 1.21e-08; MAF = 0.41, β = 0.106; n = 4,393 individuals) and a variant within ADAMTS5 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs 5; rs162500; p value = 2.11e-10; MAF = 0.005, β = -0.768; n = 4,085 pancreatic-insufficient individuals). Notably, BMI-associated variants in ADAMTS5 occur on a haplotype that is much more common in African (AFR, MAF = 0.183) than European (EUR, MAF = 0.006) populations (1000 Genomes project). A polygenic risk score (PRS) calculated using 924 SNPs (excluding 17 in FTO) showed significant association with AvgBMIz (p value = 2.2e-16; r2 = 0.03). Association between variants in FTO and the PRS correlation reveals similarities in the genetic architecture of BMI in CF and the general population. Inclusion of Black individuals in whom the single-gene disorder CF is much less common but genomic diversity is greater facilitated detection of association with variants that are in LD with functional SNPs in ADAMTS5. Our results illustrate the importance of population diversity, particularly when attempting to identify variants that manifest only under certain physiologic conditions.

Background: Limited data exist to inform antibiotic selection among people with cystic fibrosis (CF) with airway infection by multiple CF-related microorganisms. This study aimed to determine among children with CF co-infected with methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Pa) if the addition of anti-MRSA antibiotics to antipseudomonal antibiotic treatment for pulmonary exacerbations (PEx) would be associated with improved clinical outcomes compared with antipseudomonal antibiotics alone.Methods: Retrospective cohort study using data from the CF Foundation Patient Registry-Pediatric Health Information System linked dataset. The odds of returning to baseline lung function and having a subsequent PEx requiring intravenous antibiotics were compared between PEx treated with anti-MRSA and antipseudomonal antibiotics and those treated with antipseudomonal antibiotics alone, adjusting for confounding by indication using inverse probability of treatment weighting.Results: 943 children with CF co-infected with MRSA and Pa contributed 2,989 PEx for analysis. Of these, 2,331 (78%) PEx were treated with both anti-MRSA and antipseudomonal antibiotics and 658 (22%) PEx were treated with antipseudomonal antibiotics alone. Compared with PEx treated with antipseudomonal antibiotics alone, the addition of anti-MRSA antibiotics to antipseudomonal antibiotic therapy was not associated with a higher odds of returning to >90% or >100% of baseline lung function or a lower odds of future PEx requiring intravenous antibiotics. Conclusions: Children with CF co-infected with MRSA and Pa may not benefit from the addition of antiMRSA antibiotics for PEx treatment. Prospective studies evaluating optimal antibiotic selection strategies for PEx treatment are needed to optimize clinical outcomes following PEx treatment.(c) 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Background: No data exist to guide antibiotic selection among people with CF (PwCF) with respiratory cultures positive for multiple CF-related bacteria (polymicrobial infections). This study aimed to describe the number of polymicrobial in-hospital treated pulmonary exacerbations (PEx), to determine the proportion of polymicrobial PEx where antibiotics were prescribed with activity against all bacteria detected (termed complete antibiotic coverage), and to determine clinical and demographic factors associated with complete antibiotic coverage.Methods: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System dataset. Children aged 1-21 years with an in-hospital treated PEx from 2006 to 2019 were eligible for inclusion. Bacterial culture positivity was based on any positive respiratory culture in the 12 months prior to a study PEx. Results: A total of 4,923 children contributed 27,669 total PEx of which 20,214 were polymicrobial; of these, 68% of PEx had complete antibiotic coverage. In regression modeling, a prior PEx with complete antibiotic coverage for MRSA was associated with a higher likelihood of having complete antibiotic coverage at a subsequent study PEx (OR (95% CI) 3.48 (2.50, 4.83)).Conclusions: The majority of children with CF hospitalized for polymicrobial PEx were prescribed complete antibiotic coverage. Prior PEx treatment with complete antibiotic coverage predicted complete antibiotic coverage at a future PEx for all bacteria studied. Studies are needed comparing outcomes of polymicrobial PEx treated with different antibiotic coverages to optimize PEx antibiotic selection.(c) 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Background: Pulmonary exacerbations (PEx) are the most common cause of morbidity, recurrent hospitalization, and mortality in people with CF (PwCF).Lack of effective anti-inflammatory therapies for PwCF with PEx is an unmet clinical need.Corticosteroids are potent, widely available antiinflammatory drugs, but data from randomized controlled trials (RCTs) of systemic corticosteroid therapy in PwCF are limited.Methods: We performed a secondary analysis of STOP2, a large multicenter RCT of duration of antimicrobial treatment for adult PwCF presenting with PEx that included use of corticosteroids as a stratification criterion in its randomization protocol.Corticosteroid treatment effects were determined after propensity score matching for covariates such as age, sex, baseline FEV 1 , genotype, and randomization arm.The primary outcome measure was change in ppFEV 1 , with symptoms, weight, change in circulating Creactive protein concentration, time to next PEx, and adverse events included as secondary endpoints.Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated.Results: Of the 982 PEx events in randomized PwCF, corticosteroids were prescribed for 168 (17%).The decision to prescribe steroids was associated with low baseline ppFEV 1 , older age, and female sex.Co-treatment with corticosteroids did not result in greater ppFEV 1 , greater weight gain, lower CRP concentrations, longer time to next PEx, or greater symptomatic improvement than in matched PwCF receiving antibiotics alone.Steroidtreated PwCF did not experience more adverse events than controls.Conclusions: In a large RCT population, empiric physician-directed treatment with systemic corticosteroids, although common, did not improve clinical outcomes in PwCF receiving antibiotics for PEx.

Background: Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) is characterized in stages: never (prior to first positive culture) to incident (first positive culture) to chronic. The association of Pa infection stage with lung function trajectory is poorly understood and the impact of age on this association has not been examined. We hypothesized that FEV1 decline would be slowest prior to Pa infection, intermediate after incident infection and greatest after chronic Pa infection.Methods: Participants in a large US prospective cohort study diagnosed with CF prior to age 3 contributed data through the U.S. CF Patient Registry. Cubic spline linear mixed effects models were used to evaluate the longitudinal association of Pa stage (never, incident, chronic using 4 different definitions) with FEV1 adjusted for relevant covariates. Models contained interaction terms between age and Pa stage.Results: 1,264 subjects born 1992-2006 provided a median 9.5 (IQR 0.25 to 15.75) years of follow up through 2017. 89% developed incident Pa; 39-58% developed chronic Pa depending on the definition. Compared to never Pa, incident Pa infection was associated with greater annual FEV1 decline and chronic Pa infection with the greatest FEV1 decline. The most rapid FEV1 decline and strongest association with Pa infection stage was seen in early adolescence (ages 12-15).Conclusions: Annual FEV1 decline worsens significantly with each Pa infection stage in children with CF. Our findings suggest that measures to prevent chronic infection, particularly during the high-risk period of early adolescence, could mitigate FEV1 decline and improve survival.(c) 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

and increase OGTT completion rate from 5% to 20%.Eligible patients are identified by the clinical team during the weekly care conference and contacted by the clinical coordinator.After check-in and pulmonary function testing, OGTT patients are identified by the medical assistant (MA), who draws blood for the fasting PG measurement, administers the OGS, gives the patient a timer, posts the return time on the room door, and returns to the room at the conclusion of 2 hours to complete the draw.After OGTT, all patients are given a snack and encouraged to eat before driving or exercising to avoid hypoglycemia.Process facilitators include a preclinic huddle between the clinical coordinator, MAs, and clinic manager to ensure that OGS and snacks are available and that additional patient interactions are scheduled; identification of a primary and secondary MA to ensure that the 2-hour PG measurement happens on time; and provision of snacks to patients to increase satisfaction and safeguard against hypoglycemia.Conclusions: In 2022, we completed OGTT 79 times, with 40% (n = 32) occurring in clinic (42% of eligible patients screened).In the first quarter of 2023, we completed OGTT 18 times, with 55% (n = 10) occurring in clinic (11% screened).Patient response has been favorable, with two patients highlighting time saved from in-clinic OGTT in their open-ended responses to the anonymous experience of care survey.

Rationale: Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR (CF transmembrane conductance regulator) genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance. Objectives: Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity. Methods: Whole-genome sequencing data on 4,248 unique pwCF with pancreatic insufficiency and lung function measures were combined with imputed genotypes from an additional 3,592 patients with pancreatic insufficiency from the United States, Canada, and France. This report describes association of approximately 15.9 million SNPs using the quantitative Kulich normal residual mortality-adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using premodulator lung function data. Measurements and Main Results: Testing included common and rare SNPs, transcriptome-wide association, gene-level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize that these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous genome- wide association study findings. These whole-genome sequencing data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or rare variants were found. Multilocus effects at chr5p13 (SLC9A3/ CEP72) and chr11p13 ( EHF/APIP) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects. Conclusions: This premodulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and postmodulator genetic studies and the development of novel therapeutics for CF lung disease.

Rationale: Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance. Objectives: Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity. Methods: Whole genome sequencing (WGS) data on 4,248 unique pwCF with pancreatic insufficiency (PI) and lung function measures were combined with imputed genotypes from an additional 3,592 PI patients from the US, Canada, and France. This report describes association of ~15.9 million single nucleotide polymorphisms (SNPs), using the quantitative Kulich Normal Residual Mortality Adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using pre-modulator lung function data. Measurements and Main Results: Testing included common and rare SNPs, transcriptome-wide association, gene level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous GWAS findings. These WGS data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or with rare variants were found. Multi-locus effects at chr5p13 (SLC9A3/CEP72) and chr11p13 (EHF/APIP) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects. Conclusions: This pre-modulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and post-modulator genetic studies and, development of novel therapeutics for CF lung disease.

Rationale: Pulmonary exacerbation (PEx) events contribute to lung function decline in people with cystic fibrosis (CF). CF Foundation PEx guidelines note that a short course of systemic corticosteroids may offer benefit without contributing to longterm adverse effects. However, insufficient evidence exists to recommend systemic corticosteroids for PEx treatment. Objectives: To determine if systemic corticosteroids for the treatment of in-hospital pediatric PEx are associated with improved clinical outcomes compared with treatment without systemic corticosteroids. Methods: We conducted a retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked database. People with CF were included if hospitalized for a PEx between 2006 and 2018 and were 6-21 years of age. Time to next PEx was assessed by Cox proportional hazards regression. Lung function outcomes were assessed by linear mixed-effect modeling and generalized estimating equations. To address confounding by indication, inverse probability treatment weighting was used. Results: A total of 3,471 people with CF contributed 9,787 PEx for analysis. Systemic corticosteroids were used in 15% of all PEx. In our primary analysis, systemic corticosteroids were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, 20.36; 95% confidence interval [CI], 21.14, 0.42; P= 0.4) or a higher odds of returning to lung function baseline (odds ratio, 0.97; 95% CI, 0.84-1.12; P= 0.7) but were associated with a reduced chance of future PEx requiring intravenous antibiotics (hazard ratio, 0.91; 95% CI, 0.85-0.96; P= 0.002). When restricting the analysis to one PEx per person, lung function outcomes remained no different among PEx treated with or without systemic corticosteroids, but, in contrast to our primary analysis, the use of systemic corticosteroids was no longer associated with a reduced chance of having a future PEx requiring intravenous antibiotics (hazard ratio, 0.96; 95% CI, 0.86, 1.07; P= 0.42). Conclusions: Systemic corticosteroid treatment for in-hospital pediatric PEx was not associated with improved lung function outcomes. Prospective trials are needed to better evaluate the risks and benefits of systemic corticosteroid use for PEx treatment in children with CF.

patients who transferred to a different adult center, and missing outcome data.

Whole-genome sequencing (WGS) is the gold standard for fully characterizing genetic variation but is still prohibitively expensive for large samples. To reduce costs, many studies sequence only a subset of individuals or genomic regions, and genotype imputation is used to infer genotypes for the remaining individuals or regions without sequencing data. However, not all variants can be well imputed, and the current state-of-the-art imputation quality metric, denoted as standard Rsq, is poorly calibrated for lower-frequency variants. Here, we propose MagicalRsq, a machine-learning-based method that integrates variant-level imputation and population genetics statistics, to provide a better calibrated imputation quality metric. Leveraging WGS data from the Cystic Fibrosis Genome Project (CFGP), and whole-exome sequence data from UK BioBank (UKB), we performed comprehensive experiments to evaluate the performance of MagicalRsq compared to standard Rsq for partially sequenced studies. We found that MagicalRsq aligns better with true R2 than standard Rsq in almost every situation evaluated, for both European and African ancestry samples. For example, when applying models trained from 1,992 CFGP sequenced samples to an independent 3,103 samples with no sequencing but TOPMed imputation from array genotypes, MagicalRsq, compared to standard Rsq, achieved net gains of 1.4 million rare, 117k low-frequency, and 18k common variants, where net gains were gained numbers of correctly distinguished variants by MagicalRsq over standard Rsq. MagicalRsq can serve as an improved post-imputation quality metric and will benefit downstream analysis by better distinguishing well-imputed variants from those poorly imputed. MagicalRsq is freely available on GitHub.