Two-sided Confidence Intervals Research Articles

A statistical method for treating the “negative-age” and “negative-atom-number” conundrums in radioisotope dating

In radioisotope dating, statistical fluctuations of atom counts or decay counts can sometimes lead to unphysical results, such as negative counts after subtracting the background or negative apparent ages near the boundaries of the dating range. How to treat these boundary cases with a unified approach and give proper estimates on age limits and confidence intervals is an important issue in radioisotope dating. In this work, we combine the Feldman-Cousins likelihood-ratio ordering method for interval estimation, a Frequentist approach to make consistent transitions from the choice of one-sided limits to two-sided confidence intervals, and a Bayesian method to treat the background uncertainties. This data treatment method naturally eliminates the unphysical results. We use 81Kr dating and Atom Trap Trace Analysis as an example to illustrate the advantages. This method can be generalized to other radioisotopes and ultra-sensitive analysis techniques.

A better one stage multiple comparison procedure of several treatment mean lifetimes with the control for exponential distributions under heteroscedasticity

In this article, we present a new one-stage multiple comparison procedure for exponential mean lifetimes with the control under heteroscedasticity including one-sided and two-sided confidence intervals by improving the coverage probability and average confidence length compared with the old one. Users can use these simultaneous confidence intervals to identify better-than-the-control, worse-than-the-control and not-much-different-from-the-control products in agriculture, stock market, pharmaceutical industries in terms of the mean lifetimes. In the end, one example is used to demonstrate the proposed procedure.

Bioequivalence study of veterinary drugs based on oclacitinib «Nicialle» and «Apoquel» in dogs

The article presents the results of a study of the comparative pharmacokinetics (bioequivalence) of two drugs for veterinary use-the reproduced drug «Nizialle» and the original drug «Apoquel». The experiments were carried out on 12 dogs divided into two equal groups (six individuals in each). Animals of one group were given a reproduced drug orally, dogs of the other group were given a reference drug. The studied drugs were injected into the body of dogs once (individually) orally. Each animal was given a dose of each drug, corresponding to 0.6 mg oclacitinib per 1 kg of body weight. After a single administration of drugs, blood samples were taken from each dog in the group for subsequent serum collection. In the obtained blood serum samples, the content of oclacitinib was determined by highperformance liquid chromatography. The obtained values of oclacitinib concentrations served as the basis for calculating its pharmacokinetic parameters in dogs. The conducted statistical analysis showed that the two-sided confidence intervals for the Cmax, AUC0-t, AUC0-∞ ratios were in the range of 80–125%, and the Cmax/ AUC0-t ratios were in the range of 75–133%. Thus, the results of the studies demonstrated that the preparations «Apoquel» and «Nizialle» are bioequivalent.

Bootstrap Probability Errors of the Whittle MLE for Linear Regression Processes with Strongly Dependent Disturbances

This paper determines bounds on the asymptotic orders of the coverage probability errors of parametric bootstrap confidence intervals (CIs) and tests for the covariance parameters of a time series generated by a regression model with Gaussian, stationary, and strongly dependent errors. The CIs and tests are based on the plug-in Whittle maximum
 likelihood (PWML) estimators. It is shown that, under some sets of conditions on the regression coefficients, the spectral density function, and the parameter values, the bounds on the coverage probability errors of symmetric two-sided and one-sided parametric bootstrap confidence intervals on the plug-in Whittle log-likelihood function are shown to be O(n^{-3/2}\ln{n}) and O(n^{-1}\ln{n}), respectively. Apart from the \ln{n} term, the magnitudes of the coverage probability errors of the one-sided bootstrap confidence intervals for our model is shown to be essentially the same as that of the independent and identically distributed (iid) data. The error for the two-sided confidence intervals is not as small as the error O(n^{-2}) that has been established for many confidence intervals in the literature, see Hall (1992), pp 102-108.

Efficacy of a newly developed guidewire for selective biliary access

A clinical efficacy study of 0.025-inch guidewires (GWs) according to mechanical property analysis has not been reported yet. This study was designed to evaluate the clinical efficacy of a newly developed 0.025-inch GW for biliary access according to the basic mechanical property. Commercially available 0.025-inch GWs were in vitro tested based on parameters of mechanical property. Patients with naïve papilla requiring diagnostic or therapeutic ERCP were randomly assigned to an experimental 0.025-inch newly developed GW or a control 0.025-inch GW group. Technical success rate of wire-guided cannulation (WGC), difficult biliary cannulation (DBC), and adverse event rates were measured in this multicenter randomized trial. The technical success rate of primary WGC was 79.1% (151 of 191) in the experimental group and 70.8% (131 of 185) in the control group (95% two-sided confidence interval: 8.25%; p < 0.001; for a noninferiority margin of 15%). The technical success rate including cross-over to each other was also non-inferior. However, the chi-square test showed a statistical difference (81.7% vs. 68.1%; p = 0.002). Median biliary cannulation time was shorter in the experimental group (53 s vs. 77 s; p = 0.047). The rate of DBC was more frequent in the control group (34.6% vs. 50.3% p = 0.002). Multivariate analysis revealed that control group was one of contributing factors for DBC. Overall rate of post-ERCP pancreatitis was not different (4.7% vs. 8.6%; p = 0.125). WGC using a newly developed GW with superior physical performance GW in a bench test showed similar clinical efficacy and the rate of DBC was significantly lower in experimental GW.

Generalized fiducial inference for the restricted mean survival time.

The standard modeling approach for time-to-event outcomes subject to censoring is based on the hazard function, with hazard ratios capturing the effect of exposures on the risk of outcome. The restricted mean survival time, defined as the expected time to event up to a pre-specified time horizon, provides an alternative useful summary of time-to-event outcomes. Restricted mean survival time can be estimated nonparametrically and can be used to compare groups or interventions when the proportional hazards (PHs) assumption does not hold. Moreover, even when the proportional hazards assumption holds, the restricted mean survival time, an additive measure of risk, provides additional information to the hazard ratio, which is a measure of relative risk that can be difficult to interpret in absence of an estimate of the reference risk. Herein, a generalized fiducial approach is proposed for restricted mean survival time, and its asymptotic properties are investigated. Numerical simulations show the proposed approach provides one- and two-sided confidence intervals with coverage probabilities close to nominal values and controls the type-I error for two-group comparisons even for small sample sizes with a low number of events. Data from a type 1 diabetes study is used for illustration.

One-Stage Multiple Comparisons of the Mean Lifetimes of k Treatments with the Average for Exponential Distributions under Heteroscedasticity

Making use of uniformly minimum-variance unbiased estimators for the parameters of two-parameter exponential distributions and the distribution of pivotal quantities, we propose one-stage multiple comparison procedures for k mean lifetimes with the average under heteroscedasticity. The multiple comparison procedures include one-sided and two-sided confidence intervals. These intervals can be applied to identify which treatment’s mean lifetime is better than the average or worse than the average in terms of the mean lifetimes of all treatments. Critical values are obtained in order to assure users that the given confidence coefficient has been reached; they are organized in table format for practical and convenient use. An example is provided to demonstrate the proposed techniques, wherein the mean survival times of four different lung cancer categories are compared with the average.

Unbiased Variance Estimator of the Randomised Response Techniques for Population Mean

Antoch, Mola and Vozár (2022) proposed recently new randomized response technique for population mean or total of a quantitative variable. The aim of the paper is to solve the open problem to derive unbiased variance estimator of these procedures. In their proposal, unlike other randomized response techniques for population mean or total the randomized response is not a linear function of a sensitive variable. However, standard techniques to derive variance estimators in this setting are based on this assumption. That is why an interviewer needs also to know values pseudorandom numbers (i.e., results of individual randomization experiments). Respondents might perceive this relaxation of privacy protection negative. The performance of the approximate two-sided confidence intervals of distributions with different shape including their coverage is assessed by a simulation study for simple random sampling without replacement.

Study of cabozantinib in second line under real-life setting in patients with advanced renal cell carcinoma (aRCC): Study design of a French retrospective, multicenter study (OCTOPUS).

TPS744 Background: Cabozantinib is a tyrosine kinase inhibitor (TKI) directed against VEGFR, MET and AXL. In the pivotal phase III METEOR study, cabozantinib demonstrated significantly improved progression-free survival (PFS), overall response rate (ORR) and overall survival (OS) versus everolimus in patients with previously treated aRCC with clear-cell component. Thus, cabozantinib received marketing authorization from the European Medicine Agency in September 2016 for the treatment of aRCC in patients previously treated with a VEGF-targeted therapy. Cabozantinib effectiveness and safety have been investigated in several real-world evidence studies such as CABOREAL or CASSIOPE. However, many questions arising during the routine care of patients with aRCC treated by cabozantinib remain unanswered by the current literature. Therefore, the aims of OCTOPUS study are to describe the effectiveness and safety of 2nd line cabozantinib in a real-life setting in France and to address these unanswered questions in certain patients subgroups. Methods: Octopus is a multicenter (25 centers), retrospective, non-comparative, non-interventional study in patients with aRCC initiating cabozantinib in 2nd line in France. The primary endpoint is the duration of treatment (DOT) with cabozantinib: median DOT will be estimated using Kaplan Meier method. Key secondary endpoints to be assessed are: best overall response (BOR), PFS, adverse events (AEs) and subsequent treatment. DOT, BOR, PFS, safety and all baseline characteristics for each of the following subgroups will be described as exploratory endpoints: sequencing post-cabozantinib, long-responders, non-responders, cabozantinib &amp; rechallenge, cabozantinib &amp; therapeutic schedules, cabozantinib &amp; local treatment, cabozantinib &amp; elderly patients. Data will be analyzed descriptively. Due to the observational nature of this study, no formal calculation of sample size and statistical power were performed. With a sample size of 300 participants who started cabozantinib in 2nd line between 1st March 2018 and 1st March 2021 and a median DOT of 7.6 months, the two-sided confidence interval of the median will be estimated with a width equal to 1.7 months (95% Confidence Interval [CI] [6.8; 8.6]) and a censoring probability near 0. All collected data will be in accordance with the daily practice of medical doctors, with a maximum follow-up of 12-months. Data collection started in Q3 2022 and the first patient was included on September 16th 2022. No interim analysis is planned. This study is funded by Ipsen Pharma. Clinical trial information: NCT05444933 .

Delayed cutaneous hypersensitivity reactions following the use of infliximab or adalimumab in patients with coronavirus disease 2019.

Recent evidence has emerged concerning delayed cutaneous hypersensitivity reactions after infliximab or adalimumab applications in patients with coronavirus disease 2019 (COVID-19). A few real-world studies compared the events, clinical features, and prognosis of infliximab- or adalimumab-related delayed cutaneous hypersensitivity reactions in COVID-19 patients. Disproportionality analysis and Bayesian analysis were utilized to determine the suspected adverse events of delayed cutaneous hypersensitivity reactions after infliximab or adalimumab use based on the Food and Drug Administration's Adverse Event Reporting Systems (FAERS) from May 2020 to December 2021. Additionally, the times to onset and fatality rates of delayed cutaneous hypersensitivity reactions following infliximab or adalimumab were compared. In total, 475 reports of delayed cutaneous hypersensitivity reactions were associated with infliximab or adalimumab. Females were affected almost twice more than males. Among the two therapies, infliximab had the highest association with delayed cutaneous hypersensitivity reactions based on the highest reporting odds ratio (2.14, 95% two-sided confidence interval [CI] = 1.2-3.81), proportional reporting ratio (1.95, χ2 = 7.03), and empirical Bayesian geometric mean (1.94, 95% one-sided CI = 1.2). Infliximab-related delayed cutaneous hypersensitivity reactions had earlier onset (0 [interquartile range (IQR): 0-0] days vs. 166.5 (IQR: 18-889.5) days, p < 0.05), while adalimumab-related delayed cutaneous hypersensitivity reactions have higher fatality rate (0.44% vs. 0.00%). Based on the FAERS database, we profiled delayed cutaneous hypersensitivity reactions related to infliximab or adalimumab application in patients with COVID-19 with more points of occurrences, clinical characteristics, and prognosis. This article is protected by copyright. All rights reserved.

Эпидемиологическая и клиническая эффективность приема азоксимера бромида для профилактики острой респираторной инфекции и COVID-19 среди медицинских работников

Background. Acute respiratory infections (ARIs) account for over 90% of all infectious diseases in the Russian Federation. During the COVID-19 pandemic, with no causal therapy developed so far, it is important to pay attention to preventive drugs. Objective. To assess the epidemiological and clinical efficacy of azoximer bromide (Polyoxidonium®) for the prevention of ARIs and COVID-19 in the vulnerable groups (healthcare professionals). Patients and methods. We performed an observational, prospective, selective study to assess the impact of azoximer bromide (AzB) on the incidence and tolerability of ARIs and SARS-CoV-2 infection among healthcare professionals in the Russian Federation. This study was conducted between April and August 2020 and included 476 participants. Of them, 311 individuals were in the experimental group (AzB+), whereas 165 individuals served as controls (AzB-). Patients in the experimental group received 1 tablet of azoximer bromide twice a day for 10 days. We evaluated the incidence of ARIs and COVID-19 (epidemiological efficacy) and disease severity (clinical efficacy). We surveyed the participants using a special questionnaire 3 months following treatment initiation or inclusion in the control group. Statistical analysis was performed using the R v. 3.6.3 software. Differences were considered significant at p &lt; 0.05. Continuous variables were described by the number of observations (n), means, 95% confidence intervals (CIs) for means, medians (Me), and interquartile ranges (IQR). Categorical variables were presented as the absolute number of observations, percentages, and two-sided CIs. Results. We found that participants in the AzB+ group demonstrated a 43.3% lower ARI risk than controls (p &lt; 0.001). The risk of COVID-19 was decreased by 71.4% (p &lt; 0.001). We also demonstrated that AzB was effective in reducing ARI severity. Participant from the AzB+ group who developed some respiratory infections presented with a milder disease and 33.2% less common lower respiratory tract symptoms (such as cough, shortness of breath, and chest pain) (p &lt; 0.001). The incidence of pneumonia in the experimental group was 14.1% lower than that in the control group (5.3%–22.9%) (p = 0.029). Conclusion. Thus, azoximer bromide used as a preventive measure or as a part of comprehensive therapy decreased the incidence of ARIs and COVID-19 among healthcare professionals and alleviated the disease, which suggests its high epidemiological and clinical efficacy. Key words: acute respiratory infections, COVID-19, Azoximer bromide, prevention, comprehensive therapy, healthcare professionals

Parametric Analysis and Optimization of Vanillin Hydrodeoxygenation Over a Sulfided Ni-Mo/δ-Al2O3 Catalyst Under Continuous-Flow Conditions

A fundamental understanding of the process parameters affecting the catalytic hydrodeoxygenation (HDO) of bio-oils is of significance for enabling further progression and improvement of industrial biofuel upgrading methods. Herein, a novel demonstration and evaluation of the effect of temperature, pressure, and weight hourly space velocity in the continuous HDO of vanillin to cresol over a Ni-Mo/δ-Al2O3 catalyst are presented. Response surface methodology was used as a statistical experimental design method, and the application of central composite design enabled the generation of a statistically significant simulation model and a true optimization parametric study. The distribution of Ni and Mo on δ-Al2O3 was confirmed using scanning electron microscopy with energy dispersive X-ray analysis (SEM-EDX). No gradients with EDX mapping could be identified, and the elemental analysis showed well-dispersion of the metals. The mesoporous character of the catalyst-support system was unraveled using N2 physisorption. Experiments were conducted within the parametric range of 250–350 °C, 3–9 bar, and 15–35 h−1. Both temperature and pressure were found to have statistically significant linear and quadratic effects on the selectivity for cresol. The parametric interaction of temperature with pressure and space velocity also had a significant effect on the resulting response. The optimal temperature range becomes more critical at lower space velocities. Optimal selectivity for cresol was established at 314 °C, 5 bar, and 35 h−1. The fitting quality of the generated regression model was statistically confirmed and experimentally validated to describe the specified HDO process within the 95% two-sided confidence interval.

Analysis of acute pancreatitis associated with SGLT-2 inhibitors and predictive factors of the death risk: Based on food and drug administration adverse event report system database.

Background and objectives: The US FDA and Health Canada have successively published potential red flags for acute pancreatitis caused by sodium-dependent glucose transporter 2 inhibitors (SGLT-2i). However, existing studies have focused on case reports. We aimed to assess the possible association of SGLT-2i with acute pancreatitis by analyzing postmarketing adverse events reported in the FDA adverse event reporting system (FAERS), to explore risk factors for SGLT-2i-related acute pancreatitis death, and to build a nomogram. Methods and Results: We used a disproportionality analysis of suspected acute pancreatitis-related reports in the FAERS database of patients from the use of SGLT-2i from the first quarter of 2013 to the fourth quarter of 2021. Single-factor and multi-factor logistic regression analyses were performed using the relevant clinical information of patients, and risk factors were combined with the age of patients to construct a SGLT-2i risk prediction model for acute pancreatitis-related death. A total of 757 reports were retrieved. The largest number of acute pancreatitis-related cases were caused by canagliflozin (317 reports), which was also the strongest agent associated with acute pancreatitis, with the information component (IC 2.41, lower 95% one-sided confidence interval 2.16), the reporting odds ratio (ROR 5.37, 95% two-sided confidence interval 4.8-5.99), and the empirical Bayesian geometric mean (EBGM 5.32, lower 90% one-sided confidence interval 4.85). The median time to acute pancreatitis was 54 (interquartile range [IQR] 14-131) days, and approximately 83% of adverse events occurred within 6 months. Odds ratio(OR) adjusted by acute pancreatitis and the coadministration of SGLT-2i with dipeptidyl peptidase 4 inhibitor (DPP-4i), glucagon-like peptide 1 analog (GLP-1RA), and angiotensin converting enzyme inhibitor (ACEIs) was 1.39, 1.97, and 1.34, respectively, all of which were statistically significant. Logistic regression analysis showed that different SGLT-2i type and their combinations with statins were independent risk factors for acute pancreatitis mortality in the patients (p < 0.05). The mortality risk prediction model showed good discrimination and clinical applicability in both the training set (AUC 0.708) and the validation set (AUC 0.732). Conclusion: SGLT-2i may increase the risk of acute pancreatitis especially within the first 6 months of drug administration. Combination with DPP-4i, GLP-1RA or ACEIs significantly increases the risk of acute pancreatitis. In addition, different SGLT-2i type and their combination with statins are risk factors that can predict the risk of death following acute pancreatitis.

Survival Benefit of Birtamimab in Mayo Stage IV AL Amyloidosis in the Phase 3 VITAL Study Consistent after Adjustment for Key Baseline Variables

Introduction: Amyloid light chain (AL) amyloidosis - a progressive disorder caused by misfolded light chains produced by plasma cells - is associated with high mortality, poor quality of life, and increased healthcare costs, particularly in newly diagnosed patients with advanced disease (Mayo 2012 Stage IV, median overall survival <6 months). Birtamimab is a monoclonal antibody designed to neutralize circulating soluble and deplete deposited insoluble amyloid by promoting phagocytic clearance. In 2018, the Phase 3 VITAL study - a multicenter, global, randomized, double-blind, placebo-controlled study (NCT02312206) conducted in newly diagnosed, treatment-naive patients with AL amyloidosis and cardiac involvement - was terminated based on a futility analysis of the primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization ≥91 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.826 [95% CI: 0.574, 1.189]). Post hoc analysis of ACM over 9 months revealed a significant survival benefit (HR=0.413 [95% CI: 0.191, 0.895]) in patients at high risk for early death (i.e., Mayo 2012 Stage IV). Here we report the results of sensitivity analyses of ACM in the subgroup of patients with Mayo 2012 Stage IV AL amyloidosis, adjusting for key baseline variables. Methods: For ACM, the hazard ratio and 90% two-sided confidence interval were estimated from the semi-parametric Cox Regression model stratified by randomization strata (i.e., Mayo Stage I/II vs III/IV, renal stage I vs II/III, and 6MWT [6-minute walk test] distance). Separately, baseline variables including age, sex, race, ethnicity, age at diagnosis, duration since diagnosis, NT-proBNP (N-terminal pro-brain natriuretic peptide), dFLC (difference between involved and uninvolved free light chain), FLC (free light chain), NYHA (New York Heart Association) class, troponin-T, and 6MWT distance were added to the Cox Regression model to evaluate the impact on the overall survival benefit. All adjudicated deaths prior to 9 months were included in the analysis. Patients who had no events were censored at 9 months. Results: Of the 260 patients enrolled in the VITAL study, 77 (29.6%) were characterized as Mayo 2012 Stage IV at baseline, 38 randomized to birtamimab + SOC and 39 to placebo + SOC. These patients had a median age of 64 years and were primarily white (93.5%) and male (68.8%). Baseline demographic and clinical characteristics were generally balanced between the two treatment groups among these Mayo Stage IV patients. After adjustment for key baseline demographic, clinical, and laboratory variables, the adjusted hazard ratios with each of the baseline variables added separately to the Cox Regression model range from 0.336 to 0.465, with all the upper bounds of the 90% confidence interval less than 1 (Figure). Conclusions: Birtamimab is the only investigational therapeutic that has shown a significant survival benefit in Mayo Stage IV AL amyloidosis patients. The survival benefit of birtamimab was consistent across all key baseline variables, including demographic factors (age, sex, race, ethnicity), clinical characteristics (age at diagnosis, duration since diagnosis, NYHA class, 6MWT distance), and laboratory parameters (NT-proBNP, dFLC, FLC, troponin-T), reinforcing the strength of the survival data in Mayo Stage IV patients. The AFFIRM-AL study, designed to confirm the VITAL study results in Mayo Stage IV AL amyloidosis patients, is currently active and enrolling. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Partition testing for real-world evidence studies.

Traditional approaches to hypothesis testing in comparative post-approval safety and effectiveness studies of medical products are often inadequate because of a limited scope of possible inferences (e.g., superiority or inferiority). Often there is interest in simultaneously testing for superiority, equivalence, inferiority, non-inferiority, and non-superiority, which can be achieved using a partition testing framework. Partition testing only requires selection of an equivalence margin and calculation of a two-sided Wald confidence interval. In addition to permitting a broader range of inferences, the strengths of the approach include: mitigating publication bias, avoiding use of a clinically irrelevant nil hypothesis, and more transparent and impartial appraisal of the clinical importance of a study's findings by pre-specifying an equivalence margin. However, a challenge in implementing the approach can be the process for identifying an equivalence margin. The methodology is illustrated using a published study of the safety of Ondansetron for the off-label treatment of nausea and vomiting during pregnancy. Applying the method to the study results would have led to a conclusion that women exposed to Ondansetron in comparison to those that are not, are equivalent with respect to risk of cardiac malformations and oral clefts. These conclusions are more in line with the magnitude of the observed effects than the conclusions resulting from a traditional inferiority/superiority testing conducted by the study authors.

Efficacy and safety of the biosimilar denosumab candidate (Arylia) compared to the reference product (Prolia®) in postmenopausal osteoporosis: a phase III, randomized, two-armed, double-blind, parallel, active-controlled, and noninferiority clinical trial

Background/objectiveOsteoporosis is a global health concern with an increasing prevalence worldwide. Denosumab is an antiresoptive agent that has been demonstrated to be effective and safe in osteoporotic patients. This study aimed to compare the efficacy and safety of the biosimilar denosumab candidate (Arylia) to the originator product (Prolia®) in postmenopausal osteoporotic patients.MethodsIn this randomized, double-blind, active-controlled, noninferiority trial, postmenopausal osteoporotic patients received 60 mg of subcutaneous Arylia or Prolia® at months 0, 6, and 12 and were followed up for 18 months. The primary endpoint was the noninferiority of the biosimilar product to the reference product in the percentage change of bone mineral density (BMD) in 18 months at the lumbar spine (L1-L4), total hip, and femoral neck. The secondary endpoints were safety assessment, the incidence of new vertebral fractures, and the trend of bone turnover markers (BTMs).ResultsA total of 190 patients were randomized to receive either biosimilar (n = 95) or reference (n = 95) denosumab. In the per-protocol (PP) analysis, the lower limits of the 95% two-sided confidence intervals of the difference between Arylia and Prolia® in increasing BMD were greater than the predetermined noninferiority margin of − 1.78 at the lumbar spine, total hip, and femoral neck sites (mean differences [95% CIs] of 0.39 [− 1.34 to 2.11], 0.04 [− 1.61 to 1.69], and 0.41 [− 1.58 to 2.40], respectively). The two products were also comparable in terms of safety, new vertebral fractures, and trend of BTMs.ConclusionThe efficacy of the biosimilar denosumab was shown to be noninferior to that of the reference denosumab, with a comparable safety profile at 18 months.Trial registrationClinicalTrials.gov, NCT03293108; Registration date: 2017–09-19.

Effect of docetaxel (D) use on survival outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with novel hormonal therapies (NHTs): A meta-analysis.

5079 Background: ARASENS and PEACE-1 trials have shown that the addition of NHTs to D + androgen deprivation therapy (ADT) improves overall survival (OS) outcomes in mCSPC. However, whether a true synergism is present with using NHT+ADT+D is unknown due to the lack of a trial testing the efficacy of adding D to the NHT+ADT backbone. Our objective was to evaluate the survival outcomes with NHTs according to D use in mCSPC. Methods: The literature search was done from PubMed and Embase databases to identify published studies until February 12th, 2022 for meta-analysis. The MeSH search terms were “castration-sensitive prostate cancer” OR “hormone-sensitive prostate cancer” OR “hormone-naïve prostate cancer” AND “abiraterone” OR “apalutamide” OR “enzalutamide” OR “darolutamide”. The target outcome measures were progression-free survival (PFS) and OS. Generic inverse-variance method with a fixed-effects model was used, with hazard ratios with 95% two-sided confidence intervals (CI) as the principal summary measure (Review Manager software, version 5.3, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). P values below 0.05 were considered statistically significant. Results: The literature search retrieved a total of 2565 records. Six phase III studies encompassing 6701 patients evaluating survival outcomes with NHTs in mCSPC (TITAN, ARCHES, ENZAMET, LATITUDE, STAMPEDE Abi- M1, and PEACE-1) were included after filtering of the available records. Results summarized in below table. In the combined analysis, the addition of NHTs to standard of care (SOC) improved PFS and OS. PFS benefit with NHTs was similar in studies (or study subgroups) with or without D use. However the relative OS benefit with a NHT was higher in studies (or study subgroups) without D than studies permitting D (concurrent or sequential). Conclusions: In this meta-analysis, the PFS and OS benefit with NHT in mCSPC was observed independent of D use. A randomized phase III study comparing D+NHT+ADT with NHT+ADT is needed to evaluate the contribution of D to survival outcomes in patients with mCSPC receiving treatment with NHT+ADT. [Table: see text]

Fuzzy confidence interval construction and its application in recovery time for COVID-19 patients

An approach is proposed to construct fuzzy confidence intervals for unknown parameters in statistical models. In this approach, a family of confidence intervals of the unknown crisp parameter has been considered. Such confidence intervals are used to obtain a fuzzy confidence interval for the parameter of interest. ‎The proposed approach benefits a wide range of confidence intervals to obtain a trapezoidal shaped fuzzy set of the parameter space as the fuzzy confidence interval for the parameter of interest. By using the resolution identity, it is shown that the constructed fuzzy confidence intervals are really fuzzy sets of the parameter space.Some numerical examples are provided to explain the approach in one-sided and two-sided fuzzy confidence intervals. ‎‎Moreover, ‎an‎‎‎ application in health sciences ‎‎‎is provided about the ‎‎‎‎recovery time of olfactory and gustatory dysfunctions for COVID-19 patients.

MARKOV REGIME-SWITCHING MODEL DEVELOPMENT FOR NUMBER OF DEFAULTS OF INVESTMENT AND SPECULATIVE GRADE ANALYSIS

In this paper the Markov regime-switching model was constructed for the main classes of credit ratings – speculative and investment. Estimates of the model parameters were obtained based on statistics on credit ratings and the number of defaults from the annual reports of S&amp;P Global. The VIX volatility index was taken into account for a more accurate prediction of the probability of default. A similar model was constructed for the average annual value of VIX. Also a combined regime-switching model was considered, taking into account both statistics on the number of defaults of the speculative and investment grade and statistics on the average annual value of the VIX index for the period from 1990 to 2019. 10 parameters were estimated using the maximum likelihood method: the probability of the onset of a crisis and the probability of overcoming it; the probability of default in a crisis and non-crisis year for counterparties of the investment and speculative rating classes; the mathematical expectation and standard deviation of the VIX value in a crisis and non-crisis year. Two-stage backtesting of these models was carried out based on the obtained values of the parameter estimates. The first step was to check if the number of defaults falls between the quantiles of a mixed distribution consisting of a mixture of two binomials for the number of defaults and a mixture of two Gaussians for the VIX value. The second step was to check whether the number of misses in the first step falls within the two-sided confidence intervals of the binomial distribution. Finally, the number of defaults in 2020 and 2021 was forecasted and a comparison was made of the forecast for 2020 with the real numbers of defaults from the S&amp;P Global report 2020.

Non-inferiority test for a continuous variable with a flexible margin in an active controlled trial: an application to the \u201cStratall ANRS 12110 / ESTHER\u201d trial

BackgroundNon-inferiority trials are becoming increasingly popular in public health and clinical research. The choice of the non-inferiority margin is the cornerstone of such trials. Most of the time, the non-inferiority margin is fixed and constant, determined from historical trials as a fraction of the effect of the reference intervention. But in some circumstances, there may some uncertainty around the reference treatment that one would like to account for when performing the hypothesis testing. In this case, the non-inferiority margin is not fixed in advance and depends on the reference intervention estimate. Hence, the uncertainty surrounding the non-inferiority margin should be accounted for in statistical tests. In this work, we explore how to perform the non-inferiority test for a continuous variable with a flexible margin.MethodsWe have proposed in this study, two procedures for the non-inferiority test with a flexible margin for continuous endpoints. The proposed test procedures are based on a test statistic and confidence interval approaches respectively. Simulations have been used to assess the performances and properties of the proposed test procedures. An application was done on a real-world clinical data, to assess the efficacy of clinical monitoring alone versus laboratory and clinical monitoring in HIV-infected adult patients.ResultsBasically, for both proposed methods, the type I error estimate was not dependent on the values of the reference treatment. In the test statistic approach, the type 1 error rate estimate was approximatively equal to the nominal value. It has been found that the confidence interval level determined approximatively the level of significance. For a given nominal type I error α, the appropriate one- and two-sided confidence intervals should be with levels 1−α and 1−2α, respectively.ConclusionsBased on the type I error rate and power estimates, the proposed non-inferiority hypothesis test procedures had good performances and were applicable in practice.Trial registrationClinicalTrials.gov NCT00301561. Registered on March 13, 2006, url: https://clinicaltrials.gov/ct2/show/NCT00301561.