Apples to apples? Comparative analyses of national CF registries
National registries play a crucial role in understanding the natural history of cystic fibrosis (CF) and the impact of care delivery and interventions on outcomes. Data on more than 90 000 individuals are captured in CF registries around the world. Detailed examination of clinical characteristics, interventions and outcomes, benchmarking CF centres within jurisdictions and international comparisons across healthcare systems can stimulate quality improvement initiatives and drive effective changes in practice. In a 2015 crosssectional comparison of the US and the UK national CF registries, children in the US had better lung function than their UK counterparts; these differences persisted into early adulthood. However, both cohort effects and survivor bias could have affected the data interpretation as outlined in an accompanying editorial. In this issue of the Journal, addressing some of these confounders, Schluter and colleagues once again compared US and UK registry data, but this time focused on longitudinal trajectories of parallel cohorts limiting the study population to children between 6 and 18 years and those homozygous for the F508del mutation. The mean difference in per centpredicted FEV1 (ppFEV1) between the US and UK populations at ages 6, 12 and 17 years was approximately 4% 5% and 6% respectively. The data suggested that children in the US may also have a slower rate of lung function decline, but the evidence for this was less convincing and dependent on the models used. Hypothetically, if the difference of 0.13 in ppFEV1 was to be carried forward, it would take 30 years for an additional 4point difference in ppFEV1pp. The clinical importance of the difference is, therefore, questionable. Similar to the previous report, higher FEV1 outcomes in the US were not explained by differences in growth, nutrition or respiratory infections. In fact, contrary to what one would expect from the FEV1 data, children in the US were on average lighter and shorter than children in the UK during childhood and adolescence. CF care teams in the UK may be disappointed to see that previously documented differences in ppFEV1 between the cohorts persisted, so, the burning question is what are the factors responsible for these obvious differences? The authors hypothesised that a more aggressive approach to the prescription of mucoactive therapies at an earlier age in the US could drive better outcomes. In the more contemporary post 1997 birth cohort, 73% of US children were initiated on dornase alfa before the age of 6 years, compared with just 20% in the UK. A similar trend was seen for hypertonic saline. Differences in FEV1 between the cohorts were evident in children as young as 6 years, supporting the assertion that these early years are crucial for influencing the trajectory of lung disease. The progression of lung disease during the preschool years without overt clinical manifestations is well described. Research groups around the world are intensely focused on understanding and targeting early CF lung disease, but we still do not know the impact of specific therapies on longterm disease trajectory. A multisite 48week interventional clinical trial recently showed that two times per day inhaled hypertonic saline in preschool CF children improved lung function, as measured by the lung clearance index. The efficacy of dornase alfa in children less than 6 years has been less well described. The results of this study further support the rationale for prospective interventional trials to investigate the factors promoting improved lung function outcomes in young children. The CF research community is striving towards harmonisation of registries internationally, both in terms of the data collected and how data are analysed 8 but, currently, direct comparisons between national registries can be challenging. These differences can affect the estimation of countryspecific mean ppFEV1 and, therefore, interfere with an 'apples to apples' comparison of the data. It is important to appreciate that in addition to differences in healthcare delivery systems in the US and UK, the way that data are recorded in the CF registries also differs. The UK registry includes 99% of the entire national CF population, whereas only 84% of individuals with CF in the US are captured. More socially disadvantaged individuals who are predisposed to worse health outcomes may be more likely to be excluded from the registry due to the structure of the healthcare system in the US where uninsured people with CF may be underrepresented. A post hoc analysis in the previous US UK comparison by Goss et al indicated that this imbalance did not alter results but ensuring that a high proportion of the population is captured within a registry is crucial to minimise ascertainment bias and allow accurate conclusions to be drawn. Adherence to treatment in the case of high treatment burden, and low socioeconomic status are important risk factors for poor clinical outcomes, independent of the specific healthcare system, and it was not possible to account for these important factors in the analysis. The US operates an encounterbased registry, collecting information at quarterly clinic visits, whereas, in the UK, data are imputed on an annual basis only. Over the study period, children in the UK had an average of four lung function measurements reported in the registry (more have likely been performed clinically) compared with 24 measurements for US children. Schluter and colleagues used all available data rather than limiting the analysis to include just one US visit to match data collection in the UK registry, arguing that using all available data points enabled a more precise estimate of lung function trends over time. The analysis would have been more robust if encounterbased lung function data were also available for the UK cohort. It is worth remembering that the most recent data in this data set are from 6 years ago, and much may have since changed. Many children with CF in this age group will now be on dual or triple combination modulators. While differences between countries exist, it is important to appreciate that outcomes for children with CF continue to improve throughout the world and this trend is expected to continue. Given the limitations of registry data analysis, the study cannot tell us how to eliminate the observed difference. Certainly treating children of all ages with all available mucoactive agents is not the answer, especially at a time when reducing Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada CF Research Group, National Children's Research Centre, Dublin, Ireland Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland Department of Pediatrics; Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
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