UK Cystic Fibrosis Registry Research Articles

Long-Term Outcomes of Allergic Bronchopulmonary Aspergillosis and Aspergillus Colonization in Children and Adolescents with Cystic Fibrosis.

Observational studies indicate that Aspergillus colonization and allergic bronchopulmonary aspergillosis (ABPA) in people with cystic fibrosis (CF) are associated with poorer lung health and increased disease severity. We performed a longitudinal observational cohort study to analyse long-term outcomes of Aspergillus colonization and ABPA in children with CF. Anonymised UK CF Registry data from 2009 to 2019 for patients aged 8-17 years in 2009-2010 were collected. For the baseline cohort analysis, patients were classified based on the presence of Aspergillus colonization and ABPA in 2009 and/or 2010. For the longitudinal analysis, patients were categorised according to annual Aspergillus colonization and ABPA status. Comparisons made were (1) Aspergillus positive vs. negative; (2) excluding those with ABPA: Aspergillus positive vs. negative; and (3) ABPA positive vs. negative. Primary outcome was percentage predicted FEV1 decline and secondary outcomes included BMI decline, mortality, lung transplant, and IV antibiotic use. Of the 1675 children, 263 had Aspergillus colonization in the baseline cohort, 260 were diagnosed with ABPA, and 80 had both. Baseline cohort analysis showed significantly lower lung function (p < 0.0001) and increased antibiotic treatment (p < 0.001) in those with Aspergillus colonization and in those with ABPA. Longitudinal analysis showed ABPA was associated with increased decline in lung function (p < 0.00001) and BMI (p < 0.00001). Aspergillus colonization was associated with increased decline in BMI (p = 0.005) but not lung function (p = 0.30). ABPA was associated with increased decline in long-term lung function and BMI in children and young people with CF. Aspergillus colonization was associated with lower lung function at baseline, but no increased rate of decline was observed long-term.

Demographic factors associated with within-individual variability of lung function for adults with cystic fibrosis: A UK registry study

Background: Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates has not been quantified.Methods: We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1 (forced expiratory volume in 1 s) trajectories and FEV1 within-individual variability as a function of sex, age at annual review, diagnosis after first year of life, homozygous F508 genotype and birth cohort.Results: Mean FEV1 decreased with age and lung function variability showed a near-quadratic trend by age. Males showed higher FEV1 mean and variability than females across the whole age range. Earlier diagnosis and homozygous F508 genotype were also associated with higher FEV1 mean and variability. Individuals who died during follow-up showed on average higher lung function variability than those who survived.Conclusions: Key variables known to be linked with mean lung function in cystic fibrosis are also associated with an individual’s lung function variability. This work opens new avenues to understand the role played by lung function variability in disease progression and its utility in predicting key outcomes such as mortality.

P121 Updating the UK Cystic Fibrosis Registry’s genotype cleaning processes and minimising free-text to improve data quality

P121 Updating the UK Cystic Fibrosis Registry’s genotype cleaning processes and minimising free-text to improve data quality

UK Cystic Fibrosis Registry Website Enhancements: A User-Centred Approach to the Data Access Transparency

BackgroundAs a member of the HDR UK Alliance, Cystic Fibrosis Trust is committed to adopting and maintaining the transparency standards within the UK CF Registry (UKCFR). Our website is the primary source for providing information on UKCFR and data access processes. We aimed to review use and accessibility across all user groups to shape website enhancements. This project aimed to improve transparency by conducting user experience (UX) research, and based on user feedback, enhance our website. For this project, we reviewed all of the HDR UK Transparency Standards. For this poster, we will focus on Standards 3 (Clear Website Navigation and 4 (Consider Target Audience). IntroductionThe primary objective was to enhance Transparency Standards by understanding audience needs and customise website improvements based on their needs. We envisaged that the outcome would be an improved and streamlined data access process to support transparency and trust among both data applicants and the public. MethodsWe employed a multi-method approach which incorporates public involvement throughout the whole process. We conducted on-site polls to intercept website visitors and gather quick feedback during their visit. Additionally, we created and distributed targeted surveys to various groups, including public and CF professionals, to delve deeper into their website experiences. Results The website’s overall rating is high at 7.4/10. UX research respondents: public 57% public and 43% CF Professionals. The top reasons for visiting the website are accessing reports and statistics and finding out more about UK CF Registry. Ease of finding information has fairly even spread, indicating room for improvement.

Emulated trial investigating effects of multiple treatments: estimating combined effects of mucoactive nebulisers in cystic fibrosis using registry data

IntroductionPeople with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach...

Therapeutic interventions alter ecological interactions among cystic fibrosis airway microbiota.

The airways of people with cystic fibrosis (CF) often harbor a diverse microbiota and in recent years, much effort has been invested in cataloguing these. In spite of providing a wealth of insight, this cataloguing tells us little about how the organisms interact with one another in the CF airways. However, such relationships can be inferred using the theoretical framework of the Lotka-Volterra (LV) model. In the current work, we use a generalized Lotka-Volterra model to interrogate the nationwide data collected and curated by the UK CF Registry. This longitudinal dataset (covering the period 2008-2020) contains annual depositions that record the presence/absence of microbial taxa in each patient, their medication, and their CF genotype. Specifically, we wanted to identify trends in ecological relationships between the CF microbiota at a nationwide level, and whether these are potentially affected by medication. Our results show that some medications have a distinct influence on the microbial interactome, especially those that potentially influence the "gut-lung axis" or mucus viscosity. In particular, we found that patients treated with a combination of antimicrobial agents (targeting the airway microbiota), digestive enzymes (assisting in the assimilation of dietary fats and carbohydrates), and DNase (to reduce mucus viscosity) displayed a distinctly different airway interactome compared with patients treated separately with these medications.

Causal inference in survival analysis using longitudinal observational data: Sequential trials and marginal structural models.

Longitudinal observational data on patients can be used to investigate causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for estimating such effects by controlling for the time-dependent confounding that typically occurs. The most commonly used is marginal structural models (MSM) estimated using inverse probability of treatment weights (IPTW) (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, and involves creating a sequence of "trials" from new time origins and comparing treatment initiators and non-initiators. Individuals are censored when they deviate from their treatment assignment at the start of each "trial" (initiator or noninitiator), which is accounted for using inverse probability of censoring weights. The analysis uses data combined across trials. We show that the sequential trials approach can estimate the parameters of a particular MSM. The causal estimand that we focus on is the marginal risk difference between the sustained treatment strategies of "always treat" vs "never treat." We compare how the sequential trials approach and MSM-IPTW estimate this estimand, and discuss their assumptions and how data are used differently. The performance of the two approaches is compared in a simulation study. The sequential trials approach, which tends to involve less extreme weights than MSM-IPTW, results in greater efficiency for estimating the marginal risk difference at most follow-up times, but this can, in certain scenarios, be reversed at later time points and relies on modelling assumptions. We apply the methods to longitudinal observational data from the UK Cystic Fibrosis Registry to estimate the effect of dornase alfa on survival.

Assessing the health risk of living near composting facilities on lung health, fungal and bacterial disease in cystic fibrosis: a UK CF Registry study

AimTo explore the health risk of living near permitted composting sites (PCSs) on disease severity in children and adults with cystic fibrosis (CF) across the UK. MethodsA semi-individual cross-sectional study was used to examine the risk of disease severity in people with CF (pwCF) within and beyond 4 km of PCSs in the UK in 2016. All pwCF registered in the UK CF Registry were eligible for this study. Linear and Poisson regressions, adjusted for age, gender, genotype, BMI, Pseudomonas aeruginosa and deprivation, were used to quantify associations between distance to a PCS and percent predicted forced expiratory volume in one second (ppFEV1), pulmonary exacerbations (#IVdays), and fungal and bacterial infections.ResultsThe mean age of the 9,361 pwCF (3,931 children and 5,430 adults) studied was 20.1 (SD = 14.1) years; 53.3% were male; and 49.2% were homozygous F508del. Over 10% of pwCF (n = 1,015) lived within 4 km of a PCS. We found no statistically significant difference in ppFEV1 and #IVdays/year in children. However, in adults, ppFEV1 was -1.07% lower (95% confidence interval (CI): -2.29%, 0.16%) and #IVdays/year were 1.02 day higher (95%CI: 1.01, 1.04) within 4 km of a PCS. Furthermore, there were statistically significant differences in mean ppFEV1 in CF adults with Aspergillus fumigatus (58.2.% vs 62.0%, p = 0.005) and Candida spp. (56.9% vs 59.9%, p = 0.029) residing within 4 km of a PCS. No associations were identified for allergic bronchopulmonary aspergillosis, P. aeruginosa or Staphylococcus aureus.ConclusionsThis novel national study provides evidence that adults with CF living near a PCS may experience small reductions in lung function, an increased risk of pulmonary exacerbations, and more frequent fungal infections. If confirmed by studies using refined exposure assessment methods accounting for bioaerosol dispersion, these results could have important implications for the living environment of pwCF.

The risk of colorectal cancer in individuals with mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene: An English population-based study

BackgroundStudies have demonstrated a higher risk of developing colorectal cancer (CRC) in individuals with Cystic Fibrosis (CF), and also a potentially increased risk in carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. Life expectancy for those with CF is rising, increasing the number at risk of developing CRC. MethodsThe incidence of CRC amongst individuals with CF was calculated using data from CORECT-R and linked UK CF Registry and Secondary User Services (SUS) data. Crude, age-specific and age-standardised rates were compared to those without CF. The presence of CFTR mutations in individuals with CRC was assessed using 100,000 Genomes Project data. FindingsThe crude incidence rate of CRC in the CF population was 0.29 per 1,000 person-years (28 cases). The CF population were significantly younger than those without (median age at CRC diagnosis 52 years versus 73 years; p<0·01). When age-adjusted, there was a 5-fold increased CRC incidence amongst individuals with CF compared to those without (SIR 5.0 95%CI 3.2–6.9). When compared to other population studies the overall prevalence of CFTR mutations in the CRC population was significantly higher than expected (p<0·01). InterpretationCF is linked to an increased risk of CRC. The incidence of CFTR mutations in the CRC population is higher than would be expected, suggesting an association between CFTR function and CRC risk. Further research is needed to develop effective screening strategies for these populations. FundingCancer Research UK (grants C23434/A23706 & C10674/A27140)

The long-term effects of insulin use in incident cystic fibrosis-related diabetes: a target trial emulated using longitudinal national registry data.

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis and is associated with deleterious clinical outcomes. Insulin is recommended as a treatment by international guidelines. However, there are scarce clinical trial data to support the use of insulin, and little is known about the long-term outcomes of treatment. The aim of this study was to compare the long-term impacts of insulin use versus non-use in CFRD. We used data from the national UK Cystic Fibrosis Registry and adopted a target trial framework. Eligible individuals included those 12 years and older with a new diagnosis of CFRD. Outcomes were change in % predicted forced expiratory volume in 1 s (FEV1 %) and body mass index z-scores (BMI) over a 5-year follow-up period. Treatment strategies were to receive insulin or not for the duration of follow-up. Treatment effect estimates were obtained using two methods to control for confounding: inverse-probability-of-treatment weighted estimation of marginal structural models and the G-formula. We identified 1613 individuals diagnosed with CFRD between 2008 and 2016 and included 1196 and 1192 in the FEV1 % and BMI outcome analyses respectively. We found no evidence of an effect of insulin on FEV1 % over the 5-year study period. Similarly, we found no overall effect of insulin on BMI; however, there was some evidence for a positive treatment effect in patients with lower baseline BMI. Using well-established national registry data, we found no evidence of long-term treatment effects for insulin on FEV1 % or BMI in people with incident CFRD.

Mediation of the total effect of cystic fibrosis-related diabetes on mortality: A UK Cystic Fibrosis Registry cohort study.

To investigate whether the effect of cystic fibrosis-related diabetes (CFRD) on the composite outcome of mortality or transplant could act through lung function, pulmonary exacerbations and/or nutritional status. A retrospective cohort of adult cystic fibrosis (CF) patients who had not been diagnosed with CFRD were identified from the UK Cystic Fibrosis Registry (n= 2750). Rate of death or transplant was compared between patients who did and did not develop CFRD (with insulin use) during follow-up using Poisson regression, separately by sex. Causal mediation methods were used to investigate whether lung function, pulmonary exacerbations and nutritional status lie on the causal pathway between insulin-treated CFRD and mortality/transplant. At all ages, the mortality/transplant rate was higher in both men and women diagnosed with CFRD. Pulmonary exacerbations were the strongest mediator of the effect of CFRD on mortality/transplant, with an estimated 15% [95% CI: 7%, 28%] of the effect at 2 years post-CFRD diagnosis attributed to exacerbations, growing to 24% [95% CI: 9%, 46%] at 4 years post-diagnosis. Neither lung function nor nutritional status were found to be significant mediators of this effect. Estimates were similar but with wider confidence intervals in a cohort that additionally included people with CFRD but not using insulin. There is evidence that pulmonary exacerbations mediate the effect of CFRD on mortality but, as they are estimated to mediate less than one-quarter of the total effect, the mechanism through which CFRD influences survival may involve other factors.

Methods of analysis for survival outcomes with time-updated mediators, with application to longitudinal disease registry data.

Mediation analysis is a useful tool to illuminate the mechanisms through which an exposure affects an outcome but statistical challenges exist with time-to-event outcomes and longitudinal observational data. Natural direct and indirect effects cannot be identified when there are exposure-induced confounders of the mediator-outcome relationship. Previous measurements of a repeatedly-measured mediator may themselves confound the relationship between the mediator and the outcome. To overcome these obstacles, two recent methods have been proposed, one based on path-specific effects and one based on an additive hazards model and the concept of exposure splitting. We investigate these techniques, focusing on their application to observational datasets. We apply both methods to an analysis of the UK Cystic Fibrosis Registry dataset to identify how much of the relationship between onset of cystic fibrosis-related diabetes and subsequent survival acts through pulmonary function. Statistical properties of the methods are investigated using simulation. Both methods produce unbiased estimates of indirect and direct effects in scenarios consistent with their stated assumptions but, if the data are measured infrequently, estimates may be biased. Findings are used to highlight considerations in the interpretation of the observational data analysis.

P063 Physiotherapy data for the UK cystic fibrosis Registry - review and re-launch

P063 Physiotherapy data for the UK cystic fibrosis Registry - review and re-launch

Who are the 10%? - Non eligibility of cystic fibrosis (CF) patients for highly effective modulator therapies

BackgroundThe availability of mutation-specific cystic fibrosis modulator therapies has the potential to improve the lives of children and adults with cystic fibrosis. The frequency of mutations causing defects in the cystic fibrosis transmembrane conductance regulator (CFTR) function varies between sub-groups in multi-ethnic populations. The profile of patients eligible for CFTR modulator ivacaftor/tezacaftor/elexacaftor (Kaftrio™) therapy based on ethnicity has not been reported in the United Kingdom CF population. MethodsWe conducted a descriptive cross-sectional analysis of patients in the UK CF Registry who had annual review data submissions in 2019. Data analysed included demographic characteristics, spirometry, chronic Pseudomonas status, nutrition, and CF related diabetes status. The genotype data was stratified by whether there was at least one copy of F508del or no copy of F508del as current eligibility for ivacaftor/tezacaftor/elexacaftor, or projected future eligibility, is defined as having at least one copy of F508del mutation. ResultsData from 9887 patients were reviewed, 46.7% female, mean age 22.5 years. 8.6% (n = 852) patients had no copy of F508del making them ineligible for ivacaftor/tezacaftor/elexacaftor. Overall, 93.4% of patients were of white ethnicity, with a similar proportion of those with at least one F508del being white (95.6%). This was reduced to 70.0% of those with no F508del. The proportion of people of Asian ethnicity was much higher in the no F508del group (19.2% vs 1.2%). Compared with one F508del patients, the no F508del group were older (25.2 years vs 22.2 years, p < 0.001), had higher prevalence of pancreatic sufficiency (39.0% vs 14.9% p < 0.001), lower prevalence of chronic Pseudomonas infection (21.1% vs. 26.6%, p < 0.001), and higher best FEV1 from the previous year (proportion with greater than 70% FEV1 predicted, 66.1% vs 63.0%, p = 0.005). ConclusionPatients from black, Asian and minority ethnic backgrounds are significantly less likely to be eligible for ivacaftor/tezacaftor/elexacaftor based on the current prescribing policy in the UK. At present this is the most highly effective CF modulator therapy available to treat people with CF. The CF community should urgently address the unmet need for effective targeted therapies for patients without F508del.

Using Negative Control Outcomes and Difference-in-Differences Analysis to Estimate Treatment Effects in an Entirely Treated Cohort: The Effect of Ivacaftor in Cystic Fibrosis.

When an entire cohort of patients receives a treatment, it is difficult to estimate the treatment effect in the treated because there are no directly comparable untreated patients. Attempts can be made to find a suitable control group (e.g., historical controls), but underlying differences between the treated and untreated can result in bias. Here we show how negative control outcomes combined with difference-in-differences analysis can be used to assess bias in treatment effect estimates and obtain unbiased estimates under certain assumptions. Causal diagrams and potential outcomes are used to explain the methods and assumptions. We apply the methods to UK Cystic Fibrosis Registry data to investigate the effect of ivacaftor, introduced in 2012 for a subset of the cystic fibrosis population with a particular genotype, on lung function and annual rate (days/year) of receiving intravenous (IV) antibiotics (i.e., IV days). We consider 2 negative control outcomes: outcomes measured in the pre-ivacaftor period and outcomes among persons ineligible for ivacaftor because of their genotype. Ivacaftor was found to improve lung function in year 1 (an approximately 6.5–percentage-point increase in ppFEV1), was associated with reduced lung function decline (an approximately 0.5–percentage-point decrease in annual ppFEV1 decline, though confidence intervals included 0), and reduced the annual rate of IV days (approximately 60% over 3 years).

Pregnancy rates and outcomes in women with cystic fibrosis in the UK: comparisons with the general population before and after the introduction of disease-modifying treatment, 2003-17.

To compare pregnancy rates and outcomes for women with cystic fibrosis in the UK with those of the general population and assess the effect of the introduction of disease-modifying treatment. A population-based longitudinal study, 2003-17. United Kingdom. Women aged 15-44 years in the UK cystic fibrosis (CF) Registry compared with women in England and Wales. We calculated pregnancy and live-birth rates for the CF population and the general population of England and Wales. For women with CF we compared pregnancy rates before and after ivacaftor was introduced in 2013. We further used CF registry data to assess pregnancy outcomes for mothers with CF, and to assess the relationship between maternal pre-pregnancy lung function and nutritional status and child gestational age. Pregnancy and live-birth rates and child gestational age. Of 3831 women with CF, 661 reported 818 pregnancies. Compared with the general population, the pregnancy rate was 3.3 times lower in the CF population (23.5 versus 77.7 per 1000 woman-years); the live-birth rate was 3.5 times lower (17.4 versus 61.4 per 1000 woman-years) with 70% of pregnancies in CF women resulting in live births; termination of pregnancy rates were also lower (9% versus 22%). Pregnancy rates increased post-ivacaftor for eligible women with CF, from 29.7 to 45.7 per 1000 woman-years. There was no association between pre-pregnancy lung function/nutrition status and gestational age. Pregnancy rates in women with CF are about one-third of the rates in the general population with favourable outcomes, and increased for eligible women post-ivacaftor. Pregnancy rates in women with CF are about a third of the rate in England and Wales with 70% live births. Ivacaftor increases the rate.

Treatment patterns in people with cystic fibrosis: have they changed since the introduction of ivacaftor?

BackgroundIn late 2012, ivacaftor became available in the UK for people with cystic fibrosis (CF) aged 6 years and over with a G551D mutation. Long-term changes in treatment patterns have not previously been reported. We investigated long-term treatment patterns in people with CF with a G551D mutation who took ivacaftor and compared these with non-ivacaftor-treated cohorts using the UK Cystic Fibrosis Registry. MethodsUsing 2007-2018 data we compared treatment patterns between four cohorts: 1: ivacaftor-treated; 2: ivacaftor era (2013-2018), ineligible genotype (no G551D mutation); 3: pre-ivacaftor era (2007-2012), eligible genotype (G551D mutation); 4: pre-ivacaftor era, ineligible genotype. Treatments included: inhaled antibiotics, dornase alfa, hypertonic saline, chronic oral antibiotics and supplementary feeding. ResultsUp to 2012 the percentages of people taking each treatment were similar between the two cohorts defined by genotype and tended to increase by year with a similar slope. Once ivacaftor was introduced, the use of other treatments tended to decrease or remain stable by year for the ivacaftor-treated cohort, whereas it remained stable or increased in the non-ivacaftor-treated cohort. This led to differences in treatment use between the two cohorts in the ivacaftor-era, which became more marked over time. ConclusionsWe have shown a clear divergence in treatment patterns since the introduction of ivacaftor in a number of key treatments widely used in CF. Further research is needed to investigate whether the differences in treatment patterns are associated with changes in health outcomes.

Incidence and risk factors of cancer in individuals with cystic fibrosis in the UK; a case-control study

To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients with CF, registered with the UK CF Registry. Each case with a first reported cancer between 1999 and 2017 was matched with up to 4 controls: by age (±2-years) and year of cancer diagnosis. Conditional logistic regressions were adjusted for sex, lung function (FEV1%), CF related diabetes (CFRD), F508del status, transplant status, DIOS, gastro-oesophageal reflux disease, meconium ileus, Pseudomonas aeruginosa infection, pancreatic insufficiency, proton pump inhibitor (PPI) use, IV antibiotic days and BMI.Results: From 12,886 registered patients, 146 (1.1%) cases of malignancy were identified with 14.3% of cases occurring post solid organ transplant. Site of primary cancer was available for 98 patients: 22% were gastro-intestinal in origin (77% lower, 23% upper GI), 13% skin, 13% breast and 11% lymphomas/leukaemia. In univariable analysis, transplantation increased the odds of reporting any cancer by 2.46 times (95%CI: 1.3-4.6). CFRD also increased the odds of reporting any cancer (OR 2.35; CI: 1.37-4.0) and PPI use (OR 2.0; CI 1.28-3.19). In the multivariable models significant associations with CFRD and transplant remained, while PA infection, PPI use and being overweight showed increased, but statistically insignificant risks. The incidence of GI cancer was strongly associated with CFRD (OR=4.04; 1.47-11.1).Conclusions: We observed a high incidence of lower GI cancers in our cohort which was significantly affected by the presence of CFRD. Screening for gastrointestinal cancers could benefit patients at higher risk.

Using generalized linear models to implement g-estimation for survival data with time-varying confounding.

Using data from observational studies to estimate the causal effect of a time-varying exposure, repeatedly measured over time, on an outcome of interest requires careful adjustment for confounding. Standard regression adjustment for observed time-varying confounders is unsuitable, as it can eliminate part of the causal effect and induce bias. Inverse probability weighting, g-computation, and g-estimation have been proposed as being more suitable methods. G-estimation has some advantages over the other two methods, but until recently there has been a lack of flexible g-estimation methods for a survival time outcome. The recently proposed Structural Nested Cumulative Survival Time Model (SNCSTM) is such a method. Efficient estimation of the parameters of this model required bespoke software. In this article we show how the SNCSTM can be fitted efficiently via g-estimation using standard software for fitting generalised linear models.The ability to implement g-estimation for a survival outcome using standard statistical software greatly increases the potential uptake of this method. We illustrate the use of this method of fitting the SNCSTM by reanalyzing data from the UK Cystic Fibrosis Registry, and provide example R code to facilitate the use of this approach by other researchers.

Erratum to: Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry.

Erratum to: Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry.