The European Cystic Fibrosis Society Patient Registry:valuable lessons learned on how to sustain a disease registry

Background: Disease registries have the invaluable potential to provide an insight into the natural history of the disease under investigation, to provide useful information (e.g. through health indicators) for planning health care services and to identify suitable groups of patients for clinical trials enrolment. However, the establishment and maintenance of disease registries is a burdensome initiative from economical and organisational points of view and experience sharing on registries management is important to avoid waste of resources. The aim of this paper is to discuss the problems embedded in the institution and management of an international disease registry to warn against common mistakes that can derail the best of intentions: we share the experience of the European Cystic Fibrosis Society Patient Registry, which collects data on almost 30,000 patients from 23 countries. Methods: We discuss the major problems that researchers often encounter in the creation and management of disease registries: definition of the aims the registry has to reach, definition of the criteria for patients referral to the registry, definition of the information to record, set up of a data quality process, handling of missing data, maintenance of data confidentiality, regulation of data use and dissemination of research results. Results: We give examples on how many crucial aspects were solved by the European Cystic Fibrosis Society Patient Registry regarding objectives, inclusion criteria and variables definition, data management, data quality controls, missing data handling, confidentiality maintenance, data use and results dissemination. Conclusions: We suggest an extensive literature research and discussions in working groups with different stake holders, including patient representatives, on the objectives, inclusion criteria and the information to record. We propose to pilot the recording of few variables and test the applicability of their definition first. The use of a shared electronic platform for data collection that automatically computes derived variables, and automatically performs basic data quality controls is a good data management practice, that also helps in reducing missing data. We found crucial for success the collaboration with existing national and international registries, cystic fibrosis organisations and patients' associations

Introducing the Harmonic Mean Solving a Tourist’s Problem

  This exercise can be given to a group of students with basic knowledge of mathematics and physics at the beginning of a lesson. We can imagine that there will be some students that will solve the exercise using the “common sense” solution recalling basic notions of physics and some students that will solve the exercise recalling basic notion of physics and computing a mean velocity using the arithmetic mean, the most common mean. At the end of the exercise, the teacher will compare the two solutions and will present the harmonic mean as the fastest solution for the students that solved the problem using the “common sense” solution and as the correct mean to be used for the students that solved the exercise computing a mean velocit

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

<div><p>Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in <i>Cftr^F508del</i> homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the <i>F508del-CFTR</i> mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from <i>F508del</i> homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both <i>in vivo</i>, in mice, and <i>in vitro</i>, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 <i>F508del-CFTR</i> homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells <i>in vivo</i>, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of <i>TNF/TNF-alpha (tumor necrosis factor)</i> and <i>CXCL8</i> (<i>chemokine [C-X-C motif] ligand 8</i>) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the <i>F508del-CFTR</i> mutation.</p></div

CHANGES IN FEV1 PERCENT OF PREDICTED OF PEOPLE WITH CYSTIC FIBROSIS IN THE LAST DECADE: USE OF DIFFERENT STATISTICAL METHODS

Introduction Cystic fibrosis (CF) is the most common severe autosomal recessive disease in Europe, but despite remarkable improvements in health outcomes, it remains a life-shortening condition with pulmonary insufficiency as the main cause of death. Forced Expiratory Volume in 1 second compared to the predicted in a reference population (FEV1pp) is regarded as the best measure for assessing CF lung disease [1]. FEV1pp is an influential driver for defining illness stage and decisions on treatment [2] with a primary outcome measure for clinical studies and for regulatory approval of CF respiratory therapies. Aims The goal of the present work was to provide an epidemiological evaluation of changes in lung function over the last decade, which typically decreases over time, and it is linked to severity disease. To evaluate the lung function, longitudinal data of FEV1pp were used. Methods The European Cystic Fibrosis Society Patient Registry (ECFSPR) collects demographic and longitudinal clinical data of people with Cystic Fibrosis (pwCF) from 40 countries from Europe and neighbouring countries for a period spanning from 2008 to 2021 [3,4]. To have a more stable cohort we concentrate on the last decade: 2011-2021 and we excluded from the analysis: children younger than 6 years, adults older than 60 years, pwCF who had lung transplantation and pwCF from countries with less than 10 years of follow up in ECFSPR. We further selected pwCF homozygote for F508del mutation, the most frequent one in pwCF. The final study population included 18749 pwCF. We tested if changes of FEV1pp over age, included using cubic spline with 5 degrees chosen by AIC, were different according to a set of variables: chronic Pseudomonas Aeruginosa (PsA), Underweight status, Cystic Fibrosis Related Diabetes (CFRD), genotype and country group. To consider economical differences, 27 countries were classified in three groups, lower, middle, and higher income according to Gross National Income. Two regression models, including a random effect for patients and with FEV1pp as response variable, were fitted using R software: a linear mixed model (LMM) implemented with lmer function from “lme4” package and, since FEV1pp has an asymmetric distribution and it is often summarized using median and quartiles, a linear quantile mixed model (LQMM) [6] implemented with the lqmm function from “lqmm” package. Two different scenarios were explored: in the first one the year of follow-up is included as a continuous variable, in the second one it is included using dummy variables. Results The multiple regression analysis using dummy variable (Table 1) show that there was a gradual and consistent increase during the 10-year study period for FEV1pp in all age groups, but a larger increase in FEV1pp was observed in 2021 for pwCF carrying the F508del mutation when modulators, a class of drugs that act by improving production, intracellular processing, and function of the defective CFTR protein, became available for pwCF carrying this mutation. The results of the different models are comparable in terms of coefficient estimates. LMM provides a narrower confidence interval than LQMM when year is included as a continuous variable, and the linear mixed model gives a narrower Confidence Intervals when year is included as dummy variables too. The main problem in fitting models in R software on our big dataset, is the long computational time for the LQMM: the model runs for 3 minutes to obtain only coefficient estimates and approximately 5 hours to obtain a complete summary, with year included as continuous, and 1 minute for coefficient estimates only and 3 hours for a complete summary when year is insert as a dummy. The summary of this model is very demanding in terms of computational time, on the contrary, the LMM runs for only a few seconds for the coefficient estimates and for the summary. Conclusions This pan-European analysis of the ECFSPR annual data, demonstrates a consistent improvement in pulmonary function over the last decade which started even before the highly effective CFTR modulators were available. A remarkable increase in FEV1pp was observed in 2021 in pwCF who carry the F508del mutation when Elexacaftor/Tezacaftor/Ivacaftor (ETI), newest CFTR modulator drug, became available. While the findings of this study are encouraging, there are still a significant number of pwCF who cannot benefit from ETI and alternative therapeutic interventions for this group are needed. A less optimistic picture was observed in fact in low-income countries: despite the availability of the guidelines recommending standard treatments, improvement in disease outcomes was only minimal [7,8]. This registry-based study has its limitations, such as the problems with adherence to the definitions, data quality process, missing data, and data entry errors. On the other hand, over the last years, the ECFSPR introduced a data quality control project to check and reduce these limitations. Moreover, the European Medicines Agency (EMA) qualified the ECFSPR as a resource for collecting CF-specific data for Pharmacoepidemiology Studies. In conclusion, the models presented in the present study need to be additionally compared in detail for diagnostic measures, further research is needed to fulfill the unmet need of providing robust regression coefficient estimates on mixed effects models on big datasets, and simulation studies mimic real world practice are necessary

Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci

We carried out genome-wide association (GWA) studies in inbred mouse strains characterized for their lung tumor susceptibility phenotypes (spontaneous or urethane-induced) with panels of 12,959 (13K) or 138,793 (140K) single-nucleotide polymorphisms (SNPs). Above the statistical thresholds, we detected only SNP rs3681853 on Chromosome 5, two SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and SNP rs4174648 on Chromosome 16 for spontaneous tumor incidence, urethane-induced tumor incidence, and urethane-induced tumor multiplicity, respectively, with the 13K SNP panel, but only the Pas1 locus with the 140K SNP panel. Haplotype analysis carried out in the latter panel detected four additional loci. Loci reported in previous GWA studies failed to replicate. Genome-wide genetic linkage analysis in urethane-treated (BALB/c×C3H/He)F2, (BALB/c×SWR/J)F2, and (A/J×C3H/He)F2 mice showed that Pas1, but none of the other loci detected previously or herein by GWA, had a significant effect. The Lasc1 gene, identified by GWA as a functional element (Nat. Genet., 38:888–95, 2006), showed no genetic effects in the two independent intercross mouse populations containing both alleles, nor was it expressed in mouse normal lung or lung tumors. Our results indicate that GWA studies in mouse inbred strains can suffer a high rate of false-positive results and that such an approach should be used in conjunction with classical linkage mapping in genetic crosses

Epidemiology of European adults with cystic fibrosis

The European Cystic Fibrosis Society Patient Registry (ECFSPR) collects anonymised demographic and clinical data from consenting people with CF in Europe. The aim of this study is to describe the adult population with CF in Europe. We considered patients of 18 years or older in the 2017 data, the latest year of follow-up available. Countries with a coverage below 80% were not considered when reporting figures by country. Percentages are computed for categorical variables; quartiles for numerical variables. For the year 2017, the ECFSPR database contains data of 48,204 patients from 35 countries. 24,491 (51.3%) are adults. The percentage of adults varies from 6.5% in Albania to 62.8% in Sweden. The proportion of adult females varies from 37.1% in North Macedonia to 59.6% in Slovenia. The highest percentage of patients living with lung transplant is 22.7% in Slovenia. Considering patients of 18–29 years, the lowest percentage of chronic Pseudomonas Aeruginosa is 30.6% in France, the highest is 79.4% in Serbia. For chronic Burkholderia cepacia complex species the lowest percentage of infected patients is 2.5% in Italy, the highest 20.6% in Serbia. The lowest percentage of CF related diabetes is 7.3% in Slovak Republic, the highest 34.2% in the Czech Republic. Median of BMI changes from 18.8 in the Russian Federation to 22.4 kg/m2 in Luxembourg. Considering patients not transplanted, we observe a percentage of patients with FEV1% below 40% that varies from 3.0% in Denmark to 28.5% in the Russian Federation. We considered only countries with a coverage of 80% or higher, for a realistic reflection of CF and observed variation among those countries. Data show that the percentage of adult population is higher in North Europe, infections are more frequent in Eastern Europe and growth and lung function are worse in Eastern Europe. Further investigation is required to investigate differences in healthcare systems to plan an adequate development of CF care services for adult CF people

Robust Regression as a Sensible Alternative to the Weighted Ordinary Least Squares Regression in case of Heteroskedasticity. A Tutorial

Background: The robust regression is rarely used in the statistical analyses in comparison with the Ordinary Least Squares regression and the Weighted Regression. In addition, in the frequent case of the heteroskedasticity of the residuals, a weighted regression carried out once is the main suggestion of the statistical books and the resulting reduced heteroscedasticity is usually considered sufficiently satisfactory. Methods: We showed the OLS regression analysis on data simulated with a well evident heteroskedasticity and an ad hoc outlier, followed by a weighted regression iteratively carried out by using iteratively reweighted least squares, an estimation method used also in several procedures of the robust regression analysis. Therefore, the link between the iteratively performed weighted regression and the robust regression becomes immediate. Furthermore, the same data have been analysed using some robust regression procedures. Results: It has been shown that in a simulated sample of heteroscedastic data with and without an obvious artificially created outlier the weighted regression performs worse with more biased parameter estimates than robust regression procedures (such as the robust MO procedure) as the presence of the outlier is not adequately neutralized. Discussion: In presence of a heteroskedastic pattern of the residuals, the suggestion to use robust regression procedures which can also deal with the almost sure presence of outliers seems more sensible. Among the robust regression procedures carried out, the performance of the robust MO procedure appears particularly appealing since it allows biostatisticians a more reasoned management of the outliers shown in a very illustrative “ad hoc” plot. Robust regression procedures represent a sensible alternative to OLS regression taking into account that its assumptions are practically not always fulfilled and that outliers, which are almost certainly present, are not only difficult to handle in classical OLS regression but can also provide highly biased estimates

Survival estimates in European cystic fibrosis patients and the impact of socioeconomic factors: a retrospective registry cohort study

Background Median survival for cystic fibrosis (CF) patients in Europe is unknown and is likely to be influenced by socioeconomic factors. Using the European CF Society Patient Registry (ECFSPR), median survival estimates were obtained for CF patients across Europe and the impact of socioeconomic status on survival was examined. Methods CF subjects known to be alive and in the ECFSPR between 2010 and 2014 were included. Survival curves were estimated using the Kaplan–Meier method. Differences in the survival curves were assessed using the log-rank test. Cox regression was used to estimate the association between socioeconomic factors and the age-specific hazard of death, with adjustment for sex, age at diagnosis, CF transmembrane conductance regulator (CFTR) genotype and transplant status. Results The final analysis included 13 countries with 31 987 subjects (135 833 person-years of follow-up) and 1435 deaths. Median survival age for these patients in the ECFSPR was 51.7 (95% CI 50.0–53.4) years. After adjusting for potential confounders age at diagnosis, sex, CFTR genotype and transplant status, there remained strong evidence of an association between socioeconomic factors and mortality (p<0.001). Countries in the highest third of healthcare spending had a 46% lower hazard of mortality (HR 0.54, 95% CI 0.45–0.64) than countries in the lowest third of healthcare spending. Conclusions Median survival for patients with CF in Europe is comparable to that reported in other jurisdictions and differs by socioeconomic factors

Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020

Background Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). Methods We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. Results Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133). Conclusions SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination

Association of Oxygen Therapy with the Natural Disease Progression of Cystic Fibrosis: A Multi-State Model of the European Cystic Fibrosis Society Patient Registry

Background: Association between dependence on oxygen therapy (OT) and natural disease progression in people with cystic fibrosis (pwCF) has not been estimated yet. The aim of this study is to understand the prognosis for pwCF on OT, evaluating how the transition probabilities from being alive without lung transplantation (LTx) to LTx and to death, and from being alive after LTx to death change in pwCF with and without OT. Methods: We used 2008– 2017 data from the 35-country European CF Society Patient Registry. A multi-state model was fitted to assess the effects of individual risk factors on transition probabilities. Results: We considered 48,343 pwCF aged from 6 to 50 years. OT (HR 5.78, 95% CI: 5.32– 6.29) and abnormal FEV1 (HR 6.41, 95% CI: 5.28– 7.79) were strongly associated with the probability of having LTx; chronic infection with Burkholderia cepacia complex (HR 3.19, 95% CI: 2.78– 3.67), abnormal FEV1 (HR 5.00, 95% CI: 4.11– 6.08) and the need for OT (HR 4.32, 95% CI: 3.93– 4.76) showed the greatest association with the probability of dying without LTx. Once pwCF received LTx, OT (HR 1.75, 95% CI: 1.41– 2.16) and abnormal FEV1 (HR 1.63, 95% CI: 1.18– 2.25) were the main factors associated with the probability of dying. An association of gross national income with the probability of receiving LTx and with the probability of dying without LTx was also found. Conclusion: Oxygen therapy is associated with poor survival in pwCF with and without LTx; harmonization of CF care throughout European countries and minimization of the onset of pulmonary gas exchange abnormalities using all available means remains of paramount importance