SURVIVAL ANALYSIS AND REGRESSION MODELS IN THE PRESENCE OF COMPETING AND SEMI-COMPETING RISKS

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. Different survival or incidence functions can be defined in the presence of competing risks and a relevant issue is an adequate knowledge of the methodological background in order to apply a suitable statistical analysis for the study aims. This work aims at presenting different estimates of survival or incidence probabilities used in this framework. From clinical application, it emerges that crude cumulative incidence is widely diffuses both to estimate incidence probabilities and to evaluate covariate effects. On the contrary net survival functions, although of clinical interest, are not diffused because of more difficult model structure and lack of software availability. If the independence assumption between different events is tenable, Kaplan-Meier method can be used to estimate net survival. Otherwise multivariate distribution of times based on Copulas can be adopted. In the case of different causes of death, relative survival can be interpreted as net survival only under specific assumptions on the mortality pattern. A particular case on competing risks arises when only fatal events can prevent the observation of the non fatal ones, but not vice versa (semi-competing risks). The estimate of an interpretable measure of association between times to non fatal and fatal event is often of biological interest, in order to understand the disease progression. In the statistical literature some approaches have been proposed to estimate the association between two independently doubly censored failure times, but more specific approach have to be applied in the presence of semi-competing risks. After estimating the association parameter, the survival function of a non terminal event can be estimated after fixing a copula structure by means of the semi parametric methods proposed by Fine, Jiang and Chappell or the copula graphic estimator. Furthermore when the interest is to evaluate the effect of different therapeutic strategies or covariates on the occurrence of a non terminal event in a semi-competing risks setting, specific regression model have to be adopted. I propose here to adopt the methodology based on pseudo-observations, having the advantage to be implemented by generalized linear models approaches. Simulation studies are performed to compare the performances of methods to estimate the association between events, of methods based on Copulas models to estimate net survival and of regression method for net survival in the presence of semi-competing risks. A case series of breast cancer patients is used to illustrate different methods of estimating net survival functions on the causes of deaths and on the severe non fatal events in the presence of competing and semi-competing risks framework

Lung transplantation and mortality in patients with cystic fibrosis under oxygen therapy

Objectives: There are few studies about survival in patients with Cystic Fibrosis (CF) under oxygen therapy (OT). Considering its clinical meaning and impact on patients\u2019 lifestyle, we aimed to determine how OT is associated with known prognostic factors and with lung transplantation (LTx) and death (D). Methods:We considered patients 6450 years registered in the ECFSPR from 2008 to 2017. An illness-death multi-state model was fitted, denoting LTx as intermediate state. Cox\u2019s proportional hazard models were fitted using age as time scale and left truncation corresponding to age at entry into ECFSPR. Models were used to estimate transition intensities and OT hazard ratio (HR), adjusted for known prognostic factors (age, sex, insulin, Pseudomonas aeruginosa (Pa), Burkholderia cepacia (BC), BMI and FEV1% predicted). Results: 58576 patients were included in the analysis and 7627 (13%) had OT during the follow-up. 27587 (47.6%) were females, 35784 (61.1%) were <18 yrs old, 5228 (10.6%) had FEV1 <40%predicted, 5185 (9.5%) were underweight (BMI z score < 122), 6386 (10.9%) used insulin, 14037 (26.9%) had Pa, 1236 (2.4%) had BC. During the follow-up, 2509 patients had LTx and 3091 patients died: 2338 before and 753 after LTx. From the multi-state model, patients in OT have higher probability of having LTx (HR = 12.9, 95% CI: 11.6\u201314.4). The HRof death for patients in OT is 7.8 (95% CI: 6.9\u20138.7) before LTX, while it is 1.4 (95% CI: 1.2\u20131.7) after LTx. Conclusions: The need for oxygen therapy represents a turning point in patients\u2019 life, decreasing their chances of survival, with implications in the post LTX period yet. UndoubtedlyOT should be considered as a marker of CF disease severity, and patients with a supplemental oxygen requirement should have prompt and fully clinical reassessment. Preventing respiratory failure with oxygen requirement remains one of the main goals of CF care

Distribution of cystic fibrosis patients not eligible to studied CFTR modulators in Europe

Studied Cystic Fibrosis (CF) modulators have been announced to cover 90% of all CF patients. A genotype-agnostic novel therapy for CF is under development, which will focus on people with CFwho have mutations that are not eligible for the approved small molecule modulators and triple combination therapies. The data in the European Cystic Fibrosis Society Patient Registry (ECFSPR) are used to provide a quantitative overview of eligible patients. Patients who are alive and seen during the 2017, or alive and not seenwere considered (excluding France who delivered the data directly to the sponsor). Not considered were patients F508del homozygotes eligible for elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor, lumacaftor/ivacaftor, or heterozygotes eligible for elexacaftor/tezacaftor/ivacaftor. Neither were patients with at least one of the following mutations: E56 K, P67L, R74W, D110E, D110H, R117C, E193 K, L206W, R347H, R352Q, A455E, D579G, 711 +3A->G, E831X, S945L, S977F, F1052 V, K1060 T, A1067 T, R1070W, F1074L, D1152H, D1270N, 2789+5G->A, 3272-26A->G, 3849+10kbC->T (eligible for tezacaftor/ivacaftor, ivacaftor) and R117H, G178R, S549N, S549R, G551D, G551S, G1069R, R1070Q, G1244E, S1251N, S1255P, G1349D (eligible for ivacaftor). From the 41,264 patients registered in the ECFSPR for the 2017, 4,798 patients (12%) carry a genotype that is not eligible to the currentlyapproved modulators or the triple combo. The percentage of non-eligible patients varies from 2,3% in Ireland to 71,9% in Armenia. 2,954 of these patients are 11 years or older, 1,561 have a FEV1% of predicted value between 40% and 90%. In Europe approximately 88% of the patients will be eligible for the currently approved modulators or triple combo, in some countries this percentage is below 50%. With the ECFSPR data, a realistic and useful overviewcould be created to support the design of a study for patients that are not eligible to the currently available modulator and triple combination therapies

The European Cystic Fibrosis Society Patient Registry (ECFSPR) data validation programme: accuracy and consistency of data

Background: The ECFSPR database for 2016 contains data of 44,719 patients from 31 countries. Data of high quality is essential for use in annual reports and epidemiological research. Methods: A validation programme was introduced to quantify consistency and accuracy of data-input at source level, with on-site visits to countries entering data directly in the ECFSTracker software. Data fields to verify: demographic, diagnostic and transplantation, anthropometric and best lung function measurement, bacterial infections, medications and complications. Accuracy was defined as the proportion of values entered in ECFSTracker matching the medical record, and definitions used by the ECFSPR (consistency) for randomly selected cases. Results: Ten out of 41 centres (24%) in 4 countries (Austria, Portugal, Slovakia, Switzerland), reporting 6550% of all patients in their countries, were selected. Demographic, diagnostic and transplant data were checked for 489 patients (21%*), clinical data for 463 patients (20%*) (2016 data). Data on birth, gender, and transplantation exceeded 98.8% accuracy. Anomalies on reported mutations was 0.9%; reliable source data based on genetic reports, were available in 3 out of 4 countries in 95,9%- 91,9% of all patients, 55,5% in one country. Antropometry (92,2%), lung function (86,4%), inhaled antibiotics (96.1%), DNase (89.1%), pancreatic enzyme use (97.6%) were accurate and consistent with the ECFSPR definitions, so were chronic Pseudomonas (95.0%), Burkholderia infection (97.0%), and hemoptysis (94.6%). Liver disease was reported inconsistently due to different interpretation of the definition and resulted in an accuracy of 86.8%. Conclusions: The ECFSPR dataset is highly accurate for most data verified at source level. To further optimize we recommend centres to use a reliable source for genetic information, adhere to the definition of best lung function, and the ECFSPR to redefine liver disease. *of the total patients in these countries

Estimating Relapse Free Survival as a Net Probability : Regression Models and Graphical Representation : An Application of a Large Breast Cancer Case Series

In most clinical studies, the evaluation of the effect of a therapy and the impact of prognostic factors is based on relapse-free survival. Relapse free is a net survival, since it is interpreted as the relapsefree probability that would be observed if all patients experienced relapse sooner or later. Death without evidence of relapse prevents the subsequent observation of relapse, acting in a semi-competing risks framework. Relapse free survival is often estimated by standard regression models after censoring times to death. The association between relapse and death is thus accounted for. However, to better estimate relapse free survival, a bivariate distribution of times to events needs to be considered, for example by means of copula models. We concentrate here on the copula graphic estimator, for which a pertinent regression model has been developed. No direct parametric estimation of the regression coefficient for the covariates is available and the evaluation of the impact of covariates on relapse free survival is based on graphical representation for each covariate singularly. The advantage of this approach is based on the relationship between net survival, and crude cumulative incidences. Regression models can be fitted for the latter quantities and the estimates can be used to compute net survival through a copula structure. Our proposal is based on flexible regression transformation model on crude cumulative incidences based on pseudo-values. An overall view of the joint association among covariates and relapse free survival is obtained through Multiple Correspondence Analysis. Moreover cluster analysis on MCA coordinates was used to synthesize covariate patterns and to estimates the corresponding relapse free survival curve. This approach has been applied to a large \u201chistorical\u201d case series of patients with breast cancer

Investigation on Dabigatran Etexilate and Worsening of Renal Function in Patients with Atrial fibrillation : the IDEA Study

BACKGROUND AND OBJECTIVES: Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function. METHOD: One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint. RESULTS: Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury. CONCLUSIONS: Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself

Fever and pain management in childhood : Healthcare providers’ and parents’ adherence to current recommendations

In order to evaluate the adherence of healthcare providers and parents to the current recommendations concerning fever and pain management, randomized samples of 500 healthcare providers caring for children and 500 families were asked to complete an anonymous questionnaire. The 378 health care providers (HCPs) responding to the survey (75.6%) included 144 primary care pediatricians (38.1%), 98 hospital pediatricians (25.9%), 62 pediatric residents (16.4%), and 71 pediatric nurses (19.6%); the 464 responding parents (92.8%) included 175 whose youngest (or only) child was 645 years old (37.7%), 175 whose youngest (or only) child was aged 6-10 years (37.7%), and 114 whose youngest (or only) child was aged 11-14 years (24.6%). There were gaps in the knowledge of both healthcare providers and parents. Global adherence to the guidelines was lower among the pediatric nurses than the other healthcare providers (odds ratio 0.875; 95% confidence interval 0.795-0.964). Among the parents, those of children aged 6-10 and 11-14 years old, those who were older, and those without a degree answered the questions correctly significantly less frequently than the others. These findings suggest that there is an urgent need to improve the dissemination of the current recommendations concerning fever and pain management among healthcare providers and parents in order to avoid mistaken and sometimes risky attitudes, common therapeutic errors, and the unnecessary overloading of emergency department resources. Pediatric nurses and parents with older children, those who are older, and those with a lower educational level should be the priority targets of educational programmes

Autoimmunity and cytokine imbalance in inherited epidermolysis bullosa

In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1) desmoglein 3 (DSG3), bullous pemphigoid 180 (BP180), BP230 and type VII collagen (COL7), respectively). The same trend was observed for interleukin (IL)-1\u3b2, IL-2, IL-6, IL-10, tumor necrosis factor-\u3b2, and interferon-(p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively). Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS) scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively) and IL-6 (p = 0.03), whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively). This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease

Pneumococcal colonization in older adults

Background: Little is known about pneumococcal carrier states in older adults. The main aim of this study was to evaluate pneumococcal colonization patterns among older adults in two centres in Milan, Italy, before the widespread use of the 13-valent pneumococcal vaccine (PCV13) in this age group, to investigate demographic and clinical features that are associated with pneumococcal colonization and to estimate the potential coverage offered by PCV13. Results: Among 417 adults 6565 years old (171, 41.1 %, 6575 years), 41 (9.8 %) were pneumococcal carriers. Univariate and multivariate analyses revealed that pneumococcal colonization was significantly less common among individuals with underlying co-morbidities than among those without (odds ratio [OR] 0.453, 95 % confidence interval [CI] 0.235-0.875, p = 0.018; adjusted OR 0.503, 95 % CI 0.255-0.992, p = 0.047). Moreover, among these patients, those with cardiac disease had a significantly lower risk of colonization (OR 0.308, 95 % CI 0.119-0.795, p = 0.015; adjusted OR 0.341, 95 % CI 0.13-0.894, p = 0.029). Only one vaccinated subject who received 23-valent polysaccharide pneumococcal vaccine (PPV23) was colonized. Twenty-five (89.3 %) of the subjects who were <75 years old and 9 (75.0 %) of those who were 6575 years old were colonized by at least one of the serotypes that is included in PCV13, with serotype 19 F being the most common. Respiratory allergies as well as overall co-morbidities were more common in subjects who were positive for only non-PCV13 serotypes compared with negative subjects and those who were carriers of only PCV13 serotypes. Conclusions: Although this study included a relatively small number of subjects and has been performed in a limited geographic setting, results showed that pneumococcal colonization in older people is common, and the monitoring of carriers can offer useful information about the circulation of this pathogen among older people and the potential protective effect of pneumococcal vaccines. Because the colonization in most cases involves the strains that are included in PCV13, this vaccine could be useful in the prevention of pneumococcal infections in the overall population of older people. In subjects with respiratory allergies and in those with co-morbidities, the addition of the PPV23 to PCV13 should be recommended. Due to the low vaccination coverage, urgent educational programmes are required to inform older adults and their medical doctors of the risks of pneumococcal infection and the efficacy and safety of the available pneumococcal vaccines

Genetic Polymorphisms of Functional Candidate Genes and Recurrent Acute Otitis Media With or Without Tympanic Membrane Perforation

Evaluation of the genetic contribution to the development of recurrent acute otitis media (rAOM) remains challenging. This study aimed to evaluate the potential association between single nucleotide polymorphisms (SNPs) in selected genes and rAOM and to analyze whether genetic variations might predispose to the development of complicated recurrent cases, such as those with tympanic membrane perforation (TMP).A total of 33 candidate genes and 47 SNPs were genotyped in 200 children with rAOM (116 with a history of TMP) and in 200 healthy controls.INF\u3b3 rs 12369470CT was significantly less common in the children with rAOM than in healthy controls (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.25-1, P\u200a=\u200a0.04). Although not significant, interleukin (IL)-1\u3b2 rs 1143627G and toll-like receptor (TLR)-4 rs2737191AG were less frequently detected in the children with rAOM than in controls. The opposite was true for IL-8 rs2227306CT, which was found more frequently in the children with rAOM than in healthy controls. The IL-10 rs1800896TC SNP and the IL-1\u3b1 rs6746923A and AG SNPs were significantly more and less common, respectively, among children without a history of TMP than among those who suffered from this complication (OR 2.17, 95% CI 1.09-4.41, P\u200a=\u200a0.02, and OR 0.42, 95% CI 0.21-0.84, P\u200a=\u200a0.01).This study is the first report suggesting an association between variants in genes encoding for factors of innate or adaptive immunity and the occurrence of rAOM with or without TMP, which confirms the role of genetics in conditioning susceptibility to AOM