Detecting outliers and/or leverage points: a robust two-stage procedure with bootstrap cut-off points

This paper presents a robust two-stage procedure for identification of outlying observations in regression analysis. The exploratory stage identifies leverage points and vertical outliers through a robust distance estimator based on Minimum Covariance Determinant (MCD). After deletion of these points, the confirmatory stage carries out an Ordinary Least Squares (OLS) analysis on the remaining subset of data and investigates the effect of adding back in the previously deleted observations. Cut-off points pertinent to different diagnostics are generated by bootstrapping and the cases are definitely labelled as good-leverage, bad-leverage, vertical outliers and typical cases. The procedure is applied to four examples

A multinational report on SARS-CoV-2 infection outcomes in people with CF and Aspergillus infection or ABPA

Background: Aspergillus infection is known to be associated with worse respiratory outcomes in people with CF (pwCF) and is a well-recognised complication of severe SARS-CoV-2 infection. The aim of this observational cross-sectional study was to examine the association of pre-existing Aspergillus infection and/or allergic bronchopulmonary aspergillosis (ABPA) in pwCF and severity of COVID-19. Methods: Data on SARS-CoV-2 infections in pwCF from January 2020 to June 2021 were collected by the European Cystic Fibrosis Society Patient Registry. The primary outcome was COVID-19 severity measured by hospitalisation comparing those with Aspergillus infection and/or ABPA in the 12 months preceding COVID-19 and those without. Results: In total, 1095 pwCF were diagnosed with SARS-CoV-2 and information on pre-existing Aspergillus/ABPA status was available from 807. PwCF and SARS-CoV-2 in the Aspergillus/ABPA group (n = 153), in comparison to the non-Aspergillus/ABPA group (n = 654), were more likely to be hospitalised (adjusted OR 1.79 (1.19 to 2.85); p = 0.005) and their disease course was more likely to be complicated by sepsis (adjusted OR 7.78 (1.78 to 49.43); p = 0.008). The association with hospital admission was no longer significant after excluding patients with ABPA. Secondary analysis comparing pwCF who received antifungal treatment (n = 18), versus those who did not (n = 474) during COVID-19, showed a higher rate of hospitalisation (p < 0.001); intensive care unit admission (p < 0.001), and requirement for invasive ventilation (p < 0.001) in the antifungal treated group. Conclusion: We show that pre-existing Aspergillus/ABPA is associated with increased rates of hospitalisation and sepsis during COVID-19 in pwCF

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

Impact of COVID-19 infection on lung function and nutritional status amongst individuals with cystic fibrosis:A global cohort study

Background: Factors associated with severe COVID-19 infection have been identified; however, the impact of infection on longer-term outcomes is unclear. The objective of this study was to examine the impact of COVID-19 infection on the trajectory of lung function and nutritional status in people with cystic fibrosis (pwCF). Methods: This is a retrospective global cohort study of pwCF who had confirmed COVID-19 infection diagnosed between January 1, 2020 and December 31, 2021. Forced expiratory volume in one second percent predicted (ppFEV1) and body mass index (BMI) twelve months prior to and following a diagnosis of COVID-19 were recorded. Change in mean ppFEV1 and BMI were compared using a t-test. A linear mixed-effects model was used to estimate change over time and to compare the rate of change before and after infection. Results: A total of 6,500 cases of COVID-19 in pwCF from 33 countries were included for analysis. The mean difference in ppFEV1 pre- and post-infection was 1.4 %, (95 % CI 1.1, 1.7). In those not on modulators, the difference in rate of change pre- and post-infection was 1.34 %, (95 % CI -0.88, 3.56) per year (p = 0.24) and -0.74 % (-1.89, 0.41) per year (p = 0.21) for those on elexacaftor/tezacaftor/ivacaftor. No clinically significant change was noted in BMI or BMI percentile before and after COVID-19 infection. Conclusions: No clinically meaningful impact on lung function and BMI trajectory in the year following infection with COVID-19 was identified. This work highlights the ability of the global CF community to unify and address critical issues facing pwCF.</p

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

Survival Functions in the Presence of Several Events and Competing Risks: Estimation and Interpretation Beyond Kaplan- Meier

Evaluation of a therapeutic strategy is complex when the course of a disease is characterized by the occurrence of different kinds of events. Competing risks arise when the occurrence of specific events prevents the observation of other events. A particular case is semi-competing risks when only fatal events can prevent the observation of the non fatal ones.Kaplan-Meier is the most popular method to estimate overall or event free survival. On the other hand when a subset of events is considered and net survival is of concern, different estimators have been proposed. Kaplan-Meier method can be used only under the independence assumptions otherwise estimators based on multivariate distribution of times are needed. If causes of death are unknown, relative survival can approximate net survival only under specific assumptions on the mortality pattern.Kaplan-Meier method cannot be used to estimate crude cumulative incidence of specific events.The aim of this work is to present the survival functions used in competing risks framework, their non parametric estimators and semi parametric estimators for net survival based on Archimedean Copulas. This would be a help for the reader who is not experienced in competing risks analysis.A simulation study is performed to evaluate performances of net survival estimators. To illustrate survival functions in presence of different causes of death and of different kind of events a numerical example is given, a literature dataset on prostate cancer and a case series of breast cancer patients have been analysed

Factors for severe outcomes following SARS-CoV-2 infection in people with cystic fibrosis in Europe

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes. Methods: In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis. Results: Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0-18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7-35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4-17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function). Conclusion: SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes

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