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SummaryWe propose a new method to estimate the ratio between the basic reproduction numbers of a newly emerged variant and the one currently dominating. We use public data of two kinds: the proportions of the daily infected from each strain obtained from a random sample that has been sequenced, and the epidemic curves of total infections and recoveries. Our method is based on a new discrete-time SIR model with two strains, considered both in the deterministic and stochastic versions. In the deterministic case we use maximum likelihood, while in the stochastic setting, since we need to reconstruct the missing incidence and prevalence information of the new variant, we decided to use a hierarchical Bayesian hidden Markov model. This new methodology is applied to data from the Piedmont Italian region in December-January 2022, when the Omicron variant started to be observed and quickly became prevalent. With both approaches, we obtain an estimate of the contagiousness ratio that is consistent with other studies specifically designed for the aim.

In oncology, there is a growing number of therapies given in combination. Recently, several dose-finding designs for Phase I dose-escalation trials for combinations were proposed. The majority of novel designs use a pre-specified parametric model restricting the search of the target combination to a surface of a particular form. In this work, we propose a novel model-free design for combination studies, which is based on the assumption of monotonicity within each agent only. Specifically, we parametrise the ratios between each neighbouring combination by independent Beta distributions. As a result, the design does not require the specification of any particular parametric model or knowledge about increasing orderings of toxicity. We compare the performance of the proposed design to the model-based continual reassessment method for partial ordering and to another model-free alternative, the product of independent beta design. In an extensive simulation study, we show that the proposed design leads to comparable or better proportions of correct selections of the target combination while leading to the same or fewer average number of toxic responses in a trial.

Predictive probability of success is a (subjective) Bayesian evaluation of the prob- ability of a future successful event in a given state of information. In the context of pharmaceutical clinical drug development, successful events relate to the accrual of positive evidence on the therapy which is being developed, like demonstration of su- perior efficacy or ascertainment of safety. Positive evidence will usually be obtained via standard frequentist tools, according to the regulations imposed in the world of pharmaceutical development.Within a single trial, predictive probability of success can be identified with expected power, i.e. the evaluation of the success probability of the trial. Success means, for example, obtaining a significant result of a standard superiority test.Across trials, predictive probability of success can be the probability of a successful completion of an entire part of clinical development, for example a successful phase III development in the presence of phase II data.Calculations of predictive probability of success in the presence of normal data with known variance will be illustrated, both for within-trial and across-trial predictions.

This is a reader's reaction to a recent paper by E. Schechtman and G. Schechtman (Metron, 2019) about the correct definition of a concentration function for the diagnostic, i.e. supervised classification, problem. We propose and motivate a different definition and refer to the relevant literature., 8 pages

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The objective of this review is to evaluate the available evidence in order to identify an optimal de‐escalation strategy in terms of duration and type of therapy for patients with ACS treated with PCI. We will perform a NMA to appraise the safest and most efficacious combination of type and length of DAPT de‐escalation.

Squared error loss remains the most commonly used loss function for constructing a Bayes estimator of the parameter of interest. However, it can lead to sub-optimal solutions when a parameter is defined in a restricted space. It can also be an inappropriate choice in the context when an extreme overestimation and/or underestimation results in severe consequences and a more conservative estimator is preferred. We advocate a class of loss functions for parameters defined on restricted spaces which infinitely penalize boundary decisions like the squared error loss does on the real line. We also recall several properties of loss functions such as symmetry, convexity, and invariance. We propose generalizations of the squared error loss function for parameters defined on the positive real line and on an interval. We provide explicit solutions for corresponding Bayes estimators and discuss multivariate extensions. {Four} well-known Bayesian estimation problems are used to demonstrate inferential benefits the novel Bayes estimators can provide in the context of restricted estimation., Comment: 29 pages, 11 figures, 5 tables, references start at page 23

The predictive probability of success of a future clinical trial is a key quantitative tool for decision-making in drug development. It is derived from prior knowledge and available evidence, and the latter typically comes from the accumulated data on the clinical endpoint of interest in previous clinical trials. However, a surrogate endpoint could be used as primary endpoint in early development and, usually, no or limited data are collected on the clinical endpoint of interest. We propose a general, reliable, and broadly applicable methodology to predict the success of a future trial from surrogate endpoints, in a way that makes the best use of all the available evidence. The predictions are based on an informative prior, called surrogate prior, derived from the results of past trials on one or several surrogate endpoints. If available, in a Bayesian framework, this prior could be combined with data from past trials on the clinical endpoint of interest. Two methods are proposed to address a potential discordance between the surrogate prior and the data on the clinical endpoint. We investigate the patterns of behavior of the predictions in a comprehensive simulation study, and we present an application to the development of a drug in Multiple Sclerosis. The proposed methodology is expected to support decision-making in many different situations, since the use of predictive markers is important to accelerate drug developments and to select promising drug candidates, better and earlier.

This work is aimed at illustrating the strict relationship between a general definition of concentration function appeared quite some time ago on this journal and a widely used measure of the diagnostic strength of a family of binary classifiers indexed by a threshold parameter, the so-called ROC curve. The ROC curve is a common work tool in Statistics, Machine Learning and Artificial Intelligence, appearing in many applications where a binary classification (diagnosis) procedure is of interest. Hence, it is worth remarking that diagnostic strength and concentration are two sides of the same coin: the higher the concentration of one probability measure with respect to another, the higher the diagnostic strength of the likelihood ratio classification rule.

Objective This work compares two known and one novel techniques for the detection of surface EMG (sEMG) quasi-periodic burst-like signals and the estimation of their frequency. The novel method (ES) is based on the spectral analysis of the envelope signal, the other two methods use a fixed (FT) or automatically selected optimal threshold (OT). Methods The methods are compared using both simulated signals and samples of High Density sEMG experimental signals collected using electrode arrays applied to the erector spinae muscles of violinists. Results The ES method does not require thresholds. It detects presence/absence of bursts and their frequency, even in cases of a few missing bursts. It does not provide their duration. The FT method requires the selection of a fixed threshold value, estimates burst duration but is applicable only if bursts are present. The OT method identifies an optimal threshold, estimates burst duration but behaves irregularly when bursts are small or absent. Conclusions The ES method provides the estimates closest to those of an expert human counter and is not sensitive to amplitude fluctuations. It is suitable when the general bursts periodicity is of interest even if some bursts may be missing. The FT and OT methods are sensitive to amplitude fluctuations and identify random threshold crossings as bursts even when burst activity is absent. Significance Postural muscles are often activated in a burst-like fashion. The proposed ES method identifies presence/absence of bursts and their frequency, which is important for studying the neurophysiological mechanism generating them.

With the advancement of technology, analysis of large-scale data of gene expression is feasible and has become very popular in the era of machine learning. This paper develops an improved ridge approach for the genome regression modeling. When multicollinearity exists in the data set with outliers, we consider a robust ridge estimator, namely the rank ridge regression estimator, for parameter estimation and prediction. On the other hand, the efficiency of the rank ridge regression estimator is highly dependent on the ridge parameter. In general, it is difficult to provide a satisfactory answer about the selection for the ridge parameter. Because of the good properties of generalized cross validation (GCV) and its simplicity, we use it to choose the optimum value of the ridge parameter. The GCV function creates a balance between the precision of the estimators and the bias caused by the ridge estimation. It behaves like an improved estimator of risk and can be used when the number of explanatory variables is larger than the sample size in high-dimensional problems. Finally, some numerical illustrations are given to support our findings.

BACKGROUND: Although a 1-year duration of dual antiplatelet therapy (DAPT) is used in many patients after drug-eluting stent (DES) implantation, the evidence supporting this duration is uncertain. OBJECTIVES: The authors investigated the risk-benefit profile of 1-year vs≤6-month DAPT after DES using 2 novel scores to risk stratify bleeding and ischemic events. METHODS: Ischemic and bleeding risk scores were generated from ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents), a multicenter, international, "all-comers" registry that enrolled 8,665 patients treated with DES. The risk-benefit profile of 1-year vs≤6-month DAPT was then investigated across risk strata from an individual patient data pooled dataset of 7 randomized trials that enrolled 15,083 patients treated with DES. RESULTS: In the derivation cohort, the ischemic score and the bleeding score had c-indexes of 0.76 and 0.66, respectively, and both were well calibrated. In the pooled dataset, no significant difference was apparent in any ischemic endpoint between 1-year and≤6-month DAPT, regardless of the risk strata. In the overall dataset, there was no significant difference in the risk of clinically relevant bleeding between 1-year and≤6-month DAPT; however, among 2,508 patients at increased risk of bleeding, 1-year compared with≤6-month DAPT was associated with greater bleeding (HR: 2.80; 95%CI: 1.12-7.13) without a reduced risk of ischemic events in any risk strata, including those with acute coronary syndromes. These results were consistent in a network meta-analysis. CONCLUSIONS: In the present large-scale study, compared with≤6-month DAPT, a 1-year duration of DAPT was not associated with reduced adverse ischemic events in any risk strata (including acute coronary syndromes) but was associated with greater bleeding in patients at increased risk of bleeding.

Five Simple Sequence Repeats (SSRs) were used to assess the relationship between inflorescence characteristics and their allelic variation in 53 Brassica oleracea and Brassica wild relatives (n = 9). Curd morphometric traits, such as weight (CW), height (CH), diameter (CD1), shape (CS) inflorescence curvature angle (CA), and its curd stem diameter (CD2), were measured. The aim of the work was to analyze the relationships among the allelic patterns of the SSRs primers utilized, and their status of homo or heterozygosity registered at each locus, as well as the inflorescence morphometric traits in order to individuate genomic regions stimulating the hypertrophy of this reproductive organ. The relationships found explain the diversity among B. oleracea complex species (n = 9) for the inflorescence size and structure, allowing important time reduction during the breeding process by crossing wild species, transferring useful resistance, and organoleptic and nutraceutical traits. The five SSRs loci were BoABI1, BoAP1, BoPLD1, BoTHL1, and PBCGSSRBo39. According to the allelic variation ascertained, we evaluated the heterozygosity index (H) for each SSR above cited. The results showed a significant interaction between the H index of the BoPLD1 gene and the inflorescence characteristics, summarized by the First Principal Component (PC1) (p-value = 0.0244), we ascertained a negative correlation between the H index and inflorescence characteristics, namely CW, CH, CD1, CD2, CA. The homozygosity BoPLD1 alelles, indicated by the H index, affect the inflorescence characteristics and broccoli and cauliflower yields.

BACKGROUND The water load test is a simple, cheap and standardized method to evaluate gastric distension and gastric motility responses. We have previously shown that in patients with mild erosive or non-erosive esophagitis this test is frequently abnormal, suggesting an altered gastric function. The aim was to evaluate the water load test score before and after Nissen fundoplication in reflux patients. METHODS Thirty-one patients (16 men, 15 women, mean age 46.5 y) were studied before and 3 months after Nissen fundoplication by stationary esophageal manometry, wireless Bravo pH system monitoring (48 hours), and water load test. A dyspepsia symptom questionnaire was also completed before and after surgery. Data were compared with those of 35 controls. RESULTS All patients had pH-monitoring positive for pathological acid exposure and/or related-reflux symptoms in the absence of motility disorders. Basal symptoms scores were higher in patients compared to controls and improved after surgery, except than postprandial fullness, early satiation, and bloating, that were significantly increased. At baseline, all patients ingested significantly lower water volumes than controls, with a tendency to early onset of fullness and nausea, respectively. After surgery, the water volumes were significantly lower than presurgery. CONCLUSIONS In patients with reflux-related symptoms, with or without esophagitis, the water load test is frequently abnormal, suggesting an altered gastric function. Nissen fundoplication is associated with a relatively higher incidence of bloating, epigastric pain and fullness. These preliminary data could explain the incomplete resolution of symptoms after surgery in some patients, and suggest the use of additional studies to explore the gastric function in presurgical evaluation.

Aims The aim of the present study was to investigate the impact of aspirin on prognosis in takotsubo syndrome (TTS). Methods and results Patients from the International Takotsubo (InterTAK) Registry were categorized into two groups based on aspirin prescription at discharge. A comparison of clinical outcomes between groups was performed using an adjusted analysis with propensity score (PS) stratification; results from the unadjusted analysis were also reported to note the effect of the PS adjustment. Major adverse cardiac and cerebrovascular events (MACCE: a composite of death, myocardial infarction, TTS recurrence, stroke or transient ischaemic attack) were assessed at 30-day and 5-year follow-up. A total of 1533 TTS patients with known status regarding aspirin prescription at discharge were included. According to the adjusted analysis based on PS stratification, aspirin was not associated with a lower hazard of MACCE at 30-day [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.50-3.04, P = 0.64] or 5-year follow-up (HR 1.11, 95% CI 0.78-1.58, P = 0.58). These results were confirmed by sensitivity analyses performed with alternative PS-based methods, i.e. covariate adjustment and inverse probability of treatment weighting. Conclusion In the present study, no association was found between aspirin use in TTS patients and a reduced risk of MACCE at 30-day and 5-year follow-up. These findings should be confirmed in adequately powered randomized controlled trials. ClinicalTrials.gov Identifier: NCT01947621.

The primary goal of "in vitro-in vivo correlation" (IVIVC) is the reliable prediction of the in vivo serum concentration-time course, based on the in vitro drug dissolution or release profiles. IVIVC methods are particularly appropriate for formulations that are released over an extended period of time or with a lag in absorption and may support approving a change in formulation of a drug without additional bioequivalence trials in human subjects. Most of the current IVIVC models are assessed using frequentist methods, such as linear regression, based on averaged data and entail complex and potentially unstable mathematical deconvolution. The proposed IVIVC approach includes (a) a nonlinear-mixed effects model for the in vitro release data; (b) a population pharmacokinetic (PK) compartment model for the in vivo immediate release (IR) data; and (c) a system of ordinal differential equations (ODEs), containing the submodels (a) and (b), which approximates and predicts the in vivo controlled release (CR) data. The innovation in this paper consists of splitting the parameter space between submodels (a) and (b) versus (c). Subsequently, the uncertainty on these parameters is accounted for using a Bayesian framework, that is estimates from the first two submodels serve as priors for the Bayesian hierarchical third submodel. As such, the Bayesian method explained ensures a natural integration and transfer of knowledge between various sources of information, balancing possible differences in sample size and parameter uncertainty of in vitro and in vivo studies. Consequently, it is a very flexible approach yielding results for a broad range of data situations. The application of the method is demonstrated for a transdermal patch (TD).

Only an infinitesimal part of the sounds from everyday objects that surround us has been designed specifically. This study has dealt with a sensory test for sounds produced by objects interacting with other objects, which can be performed during the concept design phase, where only some parts of the product can be tested. The aim of the study has been to prove the reliability of this preliminary test and compare it to the full-product test condition. The concept for an office-chair was considered, and the sound of a chair-wheel moving across flooring tiles was tested as a simplification of chair-flooring interactions. Sixty participants took part in a listening test and described the acoustic stimuli of the wheels of two office chairs, one of high quality and the other of low quality, rolling over polyvinyl chloride (PVC), ceramic and wood floorings. The listeners were asked to assign descriptors to stimuli from a list of 26 adjectives, according to a forced ordered scale. Comparisons were made with sounds from the rolling of real office chairs. The sound of wheel rolling was prevalently judged “rough” on ceramics, “dull” on PVC and “smooth” on wood, and some cross-modal audio-tactile verbal interactions between the sounds and flooring surfaces emerged. No statistically significant difference was found between the concept and full product test conditions, thus proving the efficacy of the concept sound test during the early design phase.

Aims The differential impact on ischaemic and bleeding events of the type of drug-eluting stent [durable polymer stents [DES] vs. biodegradable polymer stents vs. bioresorbable scaffolds (BRS)] and length of dual antiplatelet therapy (DAPT) remains to be defined. Methods and results Randomized controlled trials comparing different types of DES and/or DAPT durations were selected. The primary endpoint was Major Adverse Cardiovascular Events (MACE) [a composite of death, myocardial infarction (MI), and target vessel revascularization]. Definite stent thrombosis (ST) and single components of MACE were secondary endpoints. The arms of interest were: BRS with 12 months of DAPT (12mDAPT), biodegradable polymer stent with 12mDAPT, durable polymer stent [everolimus-eluting (EES), zotarolimus-eluting (ZES)] with 12mDAPT, EES/ZES with 12 months of DAPT (DAPT > 12 m). Sixty-four studies with 150 arms and 102 735 patients were included. After a median follow-up of 20 months, MACE rates were similar in the different arms of interest. EES/ZES with DAPT > 12 m reported a lower incidence of MI than the other groups, while BRS showed a higher rate of ST when compared to EES/ZES, irrespective of DAPT length. A higher risk of major bleedings was observed for DAPT > 12 m as compared to shorter DAPT. Conclusion Durable and biodegradable polymer stents along with BRS report a similar rate of MACE irrespective of DAPT length. Fewer MI are observed with EES/ZES with DAPT > 12 m, while a higher rate of ST is reported for BRS when compared to EES/ZES, independently from DAPT length. Stent type may partially affect the outcome together with DAPT length.

Musicians activate their muscles in different patterns, depending on their posture, the instrument being played, and their experience level. Bipolar surface electrodes have been used in the past to monitor such activity, but this method is highly sensitive to the location of the electrode pair. In this work, the spatial distribution of surface EMG (sEMG) of the right trapezius and right and left erector spinae muscles were studied in 16 violin players and 11 cello players. Musicians played their instrument one string at a time in sitting position with/without backrest support. A 64 sEMG electrode (16×4) grid, 10mm inter-electrode distance (IED), was placed over the middle and lower trapezius (MT and LT) of the bowing arm. Two 16×2 electrode grids (IED=10mm) were placed on the left and right erector spinae muscles. Subjects played each of the four strings of the instrument either in large (1bow/s) or detaché tip/tail (8bows/s) bowing in two sessions (two days). In each of two days, measurements were repeated after half an hour of exercise to see the effect of exercise on the muscle activity and signal stability. A "muscle activity index" (MAI) was defined as the spatial average of the segmented active region of the RMS map. Spatial maps were automatically segmented using the watershed algorithm and thresholding. Results showed that, for violin players, sliding the bow upward from the tip toward the tail results in a higher MAI for the trapezius muscle than a downward bow. On the contrary, in cello players, higher MAI is produced in the tail to tip movement. For both instruments, an increasing MAI in the trapezius was observed as the string position became increasingly lateral, from string 1 (most medial) toward string 4 (most lateral). Half an hour of performance did not cause significant differences between the signal quality and the MAI values measured before and after the exercise. The MAI of the left and right erector spinae was smaller in the case of backrest support, especially for violin players. Back muscles of violin and cello players were activated asymmetrically, specifically in fast movements (detaché tip/tail). These findings demonstrate the sensitivity and stability of the technique and justify more extensive investigation following this proof of concept.

Background The frequency of premature atrial complexes (PACs) has been indirectly related with atrial fibrillation (AF) occurrence and adverse outcomes. Objective To evaluate whether temporal patterns of PACs are directly associated with AF onset in pacemaker patients with continuous monitoring of the atrial rhythm. Methods Overall, 193 pacemaker patients (49% female, 72±9 years old), enrolled in a national registry, were analyzed. Frequency of daily PACs was measured in a 14-day initial observation period, during which patients were in sinus rhythm. In the following period, temporal occurrence and frequency of daily PACs and eventual onset of AF were derived by pacemaker diagnostics. Results In the run-in period, median PACs frequency was 614 PACs/day (interquartile range=70–3056). Subsequently, in a median follow-up of 6 months, AF occurred in 109 patients, in particular in 37/96 (38.5%) patients with a PAC rate PACs changes daily trend before AF Conclusion PACs frequency increases in the 5–6 days preceding AF onset. A relative increase of the daily PACs is significantly associated with the risk of AF occurrence.

Drug combination trials are increasingly common nowadays in clinical research. However, very few methods have been developed to consider toxicity attributions in the dose escalation process. We are motivated by a trial in which the clinician is able to identify certain toxicities that can be attributed to one of the agents. We present a Bayesian adaptive design in which toxicity attributions are modeled via Copula regression and the maximum tolerated dose (MTD) curve is estimated as a function of model parameters. The dose escalation algorithm uses cohorts of two patients, following the continual reassessment method (CRM) scheme, where at each stage of the trial, we search for the dose of one agent given the current dose of the other agent. The performance of the design is studied by evaluating its operating characteristics when the underlying model is either correctly specified or misspecified. We show that this method can be extended to accommodate discrete dose combinations.

The dosage of prostate-specific antigen (PSA), an easily evaluable and non-invasive biomarker, has made early detection of prostate cancer (PCa) possible. However, it leads to high percentages of unnecessary biopsies and may miss aggressive tumors in men with PSA levels below 4 ng/ml. Therefore, we propose to combine circulating microRNAs (miRs) with PSA, to improve the diagnostic route for PCa. Plasma miR profiling identified candidate diagnostic miRs in a discovery cohort of 60 tumors and 60 controls (men with benign prostatic hyperplasia or healthy donors). Linear models with an empirical Bayesian approach and multivariate penalized logistic regression were applied to select tumor-associated miRs and/or clinical variables. A classifier was developed and tested on a validation cohort of 68 tumors and 174 controls consecutively collected, where miRs were evaluated by quantitative real-time polymerase chain reaction. A classifier based on miR-103a-3p, let-7a-5p and PSA could detect both overall and clinically significant tumors better than PSA alone, even in 50-69 years aged men with PSA ≤ 4 ng/ml. Even in the validation cohort, the classifier performed better than PSA alone in terms of specificity and positive predictive value, allowing to correctly identify eight out of nine tumors undetected by PSA, including three high-risk and three tumors in 50-69 years old men. Of carriers of non-malignant lesions with PSA in the 4-16 ng/ml interval, who may avoid unnecessary biopsies, 34% were correctly identified. Coupling two circulating miRs with PSA could be a useful strategy to diagnose clinically significant PCa and avoid an important fraction of unnecessary biopsies.

BACKGROUND Information on interference injuries in racehorses is lacking. OBJECTIVE To describe clinical findings and prognosis of palmar forelimb interference injuries in Standardbreds. STUDY DESIGN Retrospective cohort study. METHODS Records of 74 racehorses sustaining palmar forelimb interference injuries were studied; 7 occurred during training and 67 during racing. The number of starts before injury, hind shoeing status, gait penalties and racing speeds in cases occurring during racing were compared with negative controls (67 age, sex and speed category matched horses) from the same races. The number of starts and racing speed in 30 racing days preceding recruitment were compared with those following recruitment (negative controls) or return to racing (cases). Clinical aspects and outcome in interference-induced superficial digital flexor (SDF) tendonitis were compared with 77 horses with overstrain-induced SDF tendonitis. RESULTS In 89% of cases, there was SDF tendonitis and this was associated with a longer time to return to racing (6 months vs. 1 months; P

Introduction Different devices have been released for closure of femoral vascular access after coronary angiography or percutaneous coronary intervention, whereas evidence about their efficacy and safety when compared with manual compression or head to head is lacking, especially across different diameters of sheaths, age and sex. Results A total of 30 studies were included in the analysis. Manual compression was evaluated as the control group in all of the included studies (5620 patients), Angioseal in 15 studies (17-29) (1812 patients), Exoseal in two studies (30-31) (1773 patients), Perclose in six (29, 32-37) (849 patients), Vasoseal in eight (36, 38-43) (699 patients), DUETT in one study (44) (392 patients), StarClose in two studies (23, 45) (334 patients), Techstar in two studies (37, 46) (252 patients) and extravascular staple in one study (47) (242 patients). At network meta-analysis, all the devices resulted as not superior to manual compression to reduce all vascular complications, and these results did not vary at metaregression for age, sex and diameter of sheaths. Manual compression significantly increased time to hemostasis when compared with Femoseal (5.72; 1.91-19.10), Vasoseal (5.11; 2.32-11.33), Perclose (3.46; 1.70-7.06), Angioseal (14.95; 7.84-28.57) and Techstar (9.78; 1.81-53.65), while was similar to StarClose, DUETT and Exoseal. Conclusion Different vascular devices for closure of femoral access did not results superior to manual compression to reduce complications, whereas offered a shorted time to hemostasis. StarClose was the device with the highest probability to perform best in terms of complication, whereas Angioseal was superior in terms of reduction of time to hemostasis.

According to previous literature, we define randomized inverse sampling for comparing two treatments with respect to a binary response as the sampling that stops when a total fixed number of successes, irrespective of the treatments, are observed. We have obtained elsewhere the asymptotic distributions for the counting variables involved and have shown them to be equivalent to the corresponding asymptotic distributions for multinomial sampling. In this paper, we start deriving the same basic results using different techniques, and we then show how they give rise to genuinely novel procedures when translated into finite sample approximations. As the main example, a novel confidence interval for the logarithm of the odds ratio of two success probabilities can be constructed in the case of comparative randomized inverse sampling. Some advantages over the standard multinomial sampling in terms of coverage probabilities are visible when no adjustment for cells with zero counts is applied; otherwise, the two sampling schemes appear to be fairly equivalent. This is a reassurance that under certain circumstances, inverse sampling can be safely chosen over more traditional sampling schemes.

Evidence-based quantitative methodologies have been proposed to inform decision-making in drug development, such as metrics to make go/no-go decisions or predictions of success, identified with statistical significance of future clinical trials. While these methodologies appropriately address some critical questions on the potential of a drug, they either consider the past evidence without predicting the outcome of the future trials or focus only on efficacy, failing to account for the multifaceted aspects of a successful drug development. As quantitative benefit-risk assessments could enhance decision-making, we propose a more comprehensive approach using a composite definition of success based not only on the statistical significance of the treatment effect on the primary endpoint but also on its clinical relevance and on a favorable benefit-risk balance in the next pivotal studies. For one drug, we can thus study several development strategies before starting the pivotal trials by comparing their predictive probability of success. The predictions are based on the available evidence from the previous trials, to which new hypotheses on the future development could be added. The resulting predictive probability of composite success provides a useful summary to support the discussions of the decision-makers. We present a fictive, but realistic, example in major depressive disorder inspired by a real decision-making case.

In clinical research and in more general classification problems, a frequent concern is the reliability of a rating system. In the absence of a gold standard, agreement may be considered as an indication of reliability. When dealing with categorical data, the well-known kappa statistic is often used to measure agreement. The aim of this paper is to obtain a theoretical result about the asymptotic distribution of the kappa statistic with multiple items, multiple raters, multiple conditions, and multiple rating categories (more than two), based on recent work. The result settles a long lasting quest for the asymptotic variance of the kappa statistic in this situation and allows for the construction of asymptotic confidence intervals. A recent application to clinical endoscopy and to the diagnosis of inflammatory bowel diseases (IBDs) is shortly presented to complement the theoretical perspective.

Coronary artery disease (CAD) negatively affects prognosis in patients undergoing surgical aortic valve replacement, being currently evaluated in the most common used risk score. Our meta-analysis aims to clarify the prognostic role of CAD on mid-term survival in patients undergoing TAVI.Studies reporting multivariate predictors of adverse outcomes in patients undergoing TAVI were systematically searched for and pooled, when appropriate, using a random-effect method. 960 citations were first screened and finally 7 studies (2472 patients) were included. Diagnosis of CAD was reported in 52%(42-65) of patients and 1169 Edwards SAPIEN and 1303 CoreValve prostheses were implanted. After a median follow up of 452 days (357-585) 24% of patients (19-33) died, and 23 (14-32) for cardiovascular death. At pooled analysis of multivariate approach, diagnosis of coronary artery disease did not increase risk of death (OR 1.0, 95% CI, confidence interval, 0.67-1.50 I(2) 0%).CAD does not affect mid-term TAVI outcome: this finding should be weighted to accurately evaluate risk and strategies for patients with severe aortic stenosis.

High quality randomised clinical trials (RCTs) and meta-analysis represent the highest levels of evidence, but in everyday clinical practice, observational studies are often exploited as a quick and easy way to understand the performance of clinical and interventional strategies. In this setting, multivariate analyses are exploited to drive useful and independent information, but due to potentially confounding messages, should be critically appraised and used in everyday clinical practice.

In this paper, a new discrete statistical model for ordered categorical data is proposed via fixed-point discretization of a beta latent variable. The resulting discretized beta distribution has a highly flexible shape and it can be either over-dispersed or under-dispersed with respect to the binomial distribution. It has only two parameters, which may therefore parsimoniously depend on covariates and on random effects, providing new tools for the analysis of structured, clustered or longitudinal ordinal data. Practical examples and advices are given and an application of the new model to subjective evaluations of a gastrointestinal disease is shown.

Quantitative methodologies have been proposed to support decision making in drug development and monitoring. In particular, multicriteria decision analysis (MCDA) and stochastic multicriteria acceptability analysis (SMAA) are useful tools to assess the benefit-risk ratio of medicines according to the performances of the treatments on several criteria, accounting for the preferences of the decision makers regarding the relative importance of these criteria. However, even in its probabilistic form, MCDA requires the exact elicitations of the weights of the criteria by the decision makers, which may be difficult to achieve in practice. SMAA allows for more flexibility and can be used with unknown or partially known preferences, but it is less popular due to its increased complexity and the high degree of uncertainty in its results. In this paper, we propose a simple model as a generalization of MCDA and SMAA, by applying a Dirichlet distribution to the weights of the criteria and by making its parameters vary. This unique model permits to fit both MCDA and SMAA, and allows for a more extended exploration of the benefit-risk assessment of treatments. The precision of its results depends on the precision parameter of the Dirichlet distribution, which could be naturally interpreted as the strength of confidence of the decision makers in their elicitation of preferences.

The efficacy and safety of different statins for human immunodeficiency virus (HIV)-positive patients in the primary prevention setting remain to be established. In the present meta-analysis, 18 studies with 736 HIV-positive patients receiving combination antiretroviral therapy (cART) and treated with statins in the primary prevention setting were included (21.0% women, median age 44.1 years old). The primary endpoint was the effect of statin therapy on total cholesterol (TC) levels. Rosuvastatin 10 mg and atorvastatin 10 mg provided the largest reduction in TC levels [mean -1.67, 95% confidence interval (CI) (-1.99, -1.35) mmol/L; and mean -1.44, 95% CI (-1.85, -1.02) mmol/L, respectively]. Atorvastatin 80 mg and simvastatin 20 mg provided the largest reduction in low-density lipoprotein (LDL) [mean -2.10, 95% CI (-3.39, -0.81) mmol/L; and mean -1.57, 95% CI (-2.67, -0.47) mmol/L, respectively]. Pravastatin 10-20 mg [mean 0.24, 95% CI (0.10, 0.38) mmol/L] and atorvastatin 10 mg [mean 0.15, 95% CI (0.007, 0.23) mmol/L] had the largest increase in high-density lipoprotein, whereas atorvastatin 80 mg [mean -0.60, 95% CI (-1.09, -0.11) mmol/L] and simvastatin 20 mg [mean -0.61, 95% CI (-1.14, -0.08) mmol/L] had the largest reduction in triglycerides. The mean discontinuation rate was 0.12 per 100 person-years [95% CI (0.05, 0.20)], and was higher with atorvastatin 10 mg [26.5 per 100 person-years, 95% CI (-13.4, 64.7)]. Meta-regression revealed that nucleoside reverse transcriptase inhibitors-sparing regimens were associated with reduced efficacy for statin's ability to lower TC. Statin therapy significantly lowers plasma TC and LDL levels in HIV-positive patients and is associated with low rates of adverse events. Statins are effective and safe when dose-adjusted for drug-drug interactions with cART.

Summary The dose finding problem for single compounds has been generalized to combination therapies and several binary regression models have been proposed in the literature. We propose general tools to evaluate them, in particular dose-free parameterizations of the risks of toxicity and risk ratio functions and plots. New classes of risk functions are also proposed. They generate low dimensional parametric risk functions which are made available to the researcher and commented on for their clinical relevance.

This article is concerned with the problem of multicollinearity in the linear part of a seemingly unrelated semiparametric (SUS) model. It is also suspected that some additional non stochastic linear constraints hold on the whole parameter space. In the sequel, we propose semiparametric ridge and non ridge type estimators combining the restricted least squares methods in the model under study. For practical aspects, it is assumed that the covariance matrix of error terms is unknown and thus feasible estimators are proposed and their asymptotic distributional properties are derived. Also, necessary and sufficient conditions for the superiority of the ridge-type estimator over the non ridge type estimator for selecting the ridge parameter K are derived. Lastly, a Monte Carlo simulation study is conducted to estimate the parametric and nonparametric parts. In this regard, kernel smoothing and cross validation methods for estimating the nonparametric function are used.

Customer satisfaction data collected by a large cellular phone service provider are to be used to evaluate and improve the quality of their service. For this purpose, we propose a Bayesian treatment of a joint-response chain graph relating partial assessments of specific aspects of quality to an overall assessment of the service quality. The resulting Bayesian model can be used to render basic geographical and temporal differentiation, allowing the company to undertake direct corrective actions. Both normal and binary models are considered for our customer satisfaction data and are compared with other currently used methods in the study of customer satisfaction. Copyright © 2011 John Wiley & Sons, Ltd.

Meta-analysis is a powerful tool to summarize knowledge. Pairwise or network meta-analysis may be carried out with multivariate models that account for the dependence between treatment estimates and quantify the correlation across studies. From a different perspective, meta-analysis may be viewed as a special case of multilevel analysis having a hierarchical data structure. Hence, we introduce an alternative frequentist approach, called multilevel network meta-analysis, which also allows to account for publication bias and the presence of inconsistency. We propose our approach for a three-level data structure set-up: arms within studies at the first level, studies within study designs at the second level and design configuration at the third level. This strategy differs from the traditional frequentist modeling because it works directly on an arm-based data structure. An advantage of using multilevel analysis is its flexibility, since it naturally allows to add further levels to the model and to accommodate for multiple outcome variables. Moreover, multilevel modeling may be carried out with widely available statistical programs. Finally, we compare the results from our approach with those from a Bayesian network meta-analysis on a binary endpoint which examines the effect on mortality of some anesthetics at the longest follow-up available. In addition, we compare results from the Bayesian and multilevel network meta-analysis approaches on a publicly available "Thrombolytic drugs" database. We also provide the reader with a blueprint of SAS codes for fitting the proposed models, although our approach does not rely on any specific software.

The therapeutic potential of hematopoietic stem cell (HSC) gene therapy can be fully exploited only by reaching efficient gene transfer into HSCs without compromising their biologic properties. Although HSCs can be transduced by HIV-derived lentiviral vectors (LVs) in short ex vivo culture, they display low permissivity to the vector, requiring cytokine stimulation to reach high-frequency transduction. Using stringent assays of competitive xenograft repopulation, we show that early-acting cytokines synergistically enhanced human HSC gene transfer by LVs without impairing engraftment and repopulation capacity. Using S-phase suicide assays, we show that transduction enhancement by cytokines was not dependent on cell cycle progression and that LVs can transduce quiescent HSCs. Pharmacologic inhibition of the proteasome during transduction dramatically enhanced HSC gene transfer, allowing the reach of very high levels of vector integration in their progeny in vivo. Thus, LVs are effectively restricted at a postentry step by the activity of this proteolytic complex. Unexpectedly, cytokine stimulation rapidly and substantially down-regulated proteasome activity in hematopoietic progenitors, highlighting one mechanism by which cytokines may enhance permissiveness to LV gene transfer. These findings demonstrate that antiviral responses ultimately mediated by proteasomes strongly limit the efficiency of HSC transduction by LVs and establish improved conditions for HSC-based gene therapy.

Aims Permanent atrial fibrillation develops in many patients after ablation and pacing therapy. We compared a strategy that initially allowed patients to remain in atrial fibrillation with a strategy that initially attempted to restore and maintain sinus rhythm. Methods and Results In this multicentre randomized controlled trial, 68 patients affected by severely symptomatic paroxysmal atrial fibrillation were assigned, after successful atrioventricular junction ablation and pacing treatment, to antiarrhythmic drug therapy with amiodarone, propafenone, flecainide or sotalol and were compared with 69 patients assigned, after successful AV junction ablation and pacing treatment, to no antiarrhythmic drug therapy. The patients were followed-up for 12 to 24 months (mean 16±4). The drug arm patients had a 57% reduction in the risk of developing permanent atrial fibrillation (21% vs 37%, P =0·02). Evaluation after 12 months revealed similar quality of life scores and echocardiographic parameters in the two groups, but the drug arm patients had more episodes of heart failure and hospitalizations ( P =0·05). The outcome was similar between the 40 patients who developed permanent atrial fibrillation and the 97 who did not. Conclusion Conventional antiarrhythmic therapy reduces the risk of development of permanent atrial fibrillation after ablation and pacing therapy. The present data do not support the concept that the development of permanent atrial fibrillation is related to an adverse outcome when a perfect control of heart rate is obtained by ablation and pacing. Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved