Impact of onabotulinumtoxinA on quality of life and practical aspects of daily living : a pooled analysis of two randomized controlled trials

Objective: To evaluate the impact of onabotulinumtoxinA on individual domains of the quality of life questionnaires in a pooled analysis of two phase 3 trials in overactive bladder patients with urinary incontinence who were inadequately managed by >= 1 anticholinergic. Methods: Patients received intradetrusor injections of onabotulinumtoxinA 100U (n = 557) or placebo (n = 548). The proportions of patients with a positive response (condition "greatly improved" or "improved") on the Treatment Benefit Scale, and changes in Incontinence Quality of Life scores and King's Health Questionnaire domain scores were analyzed in the overall population and subgroups with clean intermittent catheterization use and urinary tract infection status during the first 12 weeks of treatment. Responses to individual King's Health Questionnaire items were also assessed. Results: Significantly greater proportions of onabotulinumtoxinA-treated patients achieved positive Treatment Benefit Scale response versus placebo (61.8% vs 28.0%; P < 0.001). OnabotulinumtoxinA showed significantly greater improvements versus placebo in Incontinence Quality of Life total (22.5 vs 6.6), Incontinence Quality of Life subscale scores and all domains of the King's Health Questionnaire. Notably, a similar trend was observed regardless of clean intermittent catheterization/urinary tract infection status. Additionally, onabotulinumtoxinA resulted in significantly greater improvements than the placebo in practical aspects of patients daily lives, including pad use, need to change undergarments, sleep, relationship with partner and work life/daily activities. Conclusion: In overactive bladder patients with urinary incontinence, onabotulinumtoxinA 100U demonstrated significant improvements across the individual domains of the quality of life questionnaires, regardless of clean intermittent catheterization or urinary tract infection status, and provided a positive impact on practical aspects of patients' daily lives

Mapping EQ-5D Utility Scores from the Incontinence Quality of Life Questionnaire among Patients with Neurogenic and Idiopathic Overactive Bladder

AbstractObjectivesTo provide a mapping algorithm for estimating EuroQol five-dimensional (EQ-5D) questionnaire index scores from the Incontinence-specific Quality of Life questionnaire (I-QOL) based on nationally representative samples of patients with idiopathic or neurogenic overactive bladder (OAB) using EQ-5D questionnaire preference valuations based on both the UK and US general populations.MethodsAnalyses were conducted for 2505 patients from the Adelphi Overactive Bladder Disease Specific Programme, a cross-sectional study of patients with idiopathic or neurogenic OAB, undertaken in the United States and Europe in 2010. A range of statistical modeling techniques was used. Tenfold cross-validation techniques were used to calculate mean absolute error (MAE) and root mean squared error (RMSE) goodness-of-fit statistics. Various predictor lists, together with a method combining stepwise selection with multivariable fractional polynomial techniques to allow nonlinear relationships to feature, were pursued.ResultsChoice of predictors was consistent for both the UK and US EQ-5D questionnaire tariffs. For idiopathic, the best model included the I-QOL total score and age (both modeled nonlinearly.) For neurogenic, the best model was the I-QOL social embarrassment domain score modeled linearly only. Best-fit results were better in the idiopathic (n = 2351; MAE = 0.10; RMSE = 0.14) than in the neurogenic sample (n = 254; MAE = 0.17; RMSE = 0.22).ConclusionsThis research provides algorithms for mapping EQ-5D questionnaire index scores from the I-QOL, allowing calculation of appropriate preference-based health-related quality-of-life scores for use in cost-effectiveness analyses when only I-QOL data are available. The strongest results were for idiopathic patients, but those for neurogenic are consistent with those of other published mapping studies

OnabotulinumtoxinA in the treatment of overactive bladder:a cost-effectiveness analysis versus best supportive care in England and Wales

The cost-effectiveness of onabotulinumtoxinA (BOTOX®) 100 U + best supportive care (BSC) was compared with BSC alone in the management of idiopathic overactive bladder in adult patients who are not adequately managed with anticholinergics. BSC included incontinence pads and, for a proportion of patients, anticholinergics and/or occasional clean intermittent catheterisation. A five-state Markov model was used to estimate total costs and outcomes over a 10-year period. The cohort was based on data from two placebo-controlled trials and a long-term extension study of onabotulinumtoxinA. After discontinuation of initial treatment, a proportion of patients progressed to downstream sacral nerve stimulation (SNS). Cost and resource use was estimated from a National Health Service perspective in England and Wales using relevant reference sources for 2012 or 2013. Results showed that onabotulinumtoxinA was associated with lower costs and greater health benefits than BSC in the base case, with probabilistic sensitivity analysis indicating an 89 % probability that the incremental cost-effectiveness ratio would fall below £20,000. OnabotulinumtoxinA remained dominant over BSC in all but two scenarios tested; it was also economically dominant when compared directly with SNS therapy. In conclusion, onabotulinumtoxinA appears to be a cost-effective treatment for overactive bladder compared with BSC alone

Development of the Incontinence Utility Index: estimating population-based utilities associated with urinary problems from the Incontinence Quality of Life Questionnaire and Neurogenic Module

BACKGROUND: Generic utility instruments may not fully capture the impact and consequences of urinary problems. Condition-specific preference-based measures, developed from previously validated disease-specific patient-reported outcomes instruments, may add relevant information for economic evaluations. The aim of this study was to develop a condition-specific preference-based measure, the Incontinence Utility Index (IUI), for valuing health states associated with urinary problems. METHODS: A two-step process was implemented. First, an abbreviated health state classification system was developed from the Incontinence Quality of Life Questionnaire (I-QOL) and Neurogenic Module by applying Rasch modelling, classical psychometrical testing and expert criteria to data from two pivotal trials comprised of neurogenic detrusor overactivity (NDO) patients. Criterion, convergent validity and concordance with the original instrument was assessed in the abbreviated version. Then, a multi-attribute utility function (MAUF) was estimated from a representative sample of the UK non-institutionalized adult general population. Visual analogue and time-trade off (TTO) evaluations were applied in the elicitation process. Predictive validity of the MAUF was tested comparing estimated and direct utility scores. RESULTS: The abbreviated health state classification system generated from the NDO sample contained 5 attributes with 3 levels of response and had adequate psychometrical properties: significant differences in scores according to the reduction in the frequency of urinary incontinence episodes [UIE] (p < 0.001); Spearman correlation coefficient with number of daily UIE = −0.43; p < 0.01 and Intraclass Correlation Coefficient (ICC, 95% CI) with the original version = 0.90 (0.89-0.91; p < 0.001). Next, 442 participants were interviewed (398 cases were valid, generating 2,388 TTO evaluations) to estimate the social preferences for derived health states. Mean age was 44.75 years (interquartile range 33.5-55.5) and 60.1% were female. An overall algorithm for the IUI was estimated and transformed onto a dead = 0.00 and full health = 1.00 scale. Model fits were acceptable (R-squared = 0.923 and 0.978). Predictive validity was adequate: ICC (95% CI) = 0.928 (0.648-0.985) and Mean of Absolute Differences = 0.038. CONCLUSIONS: The newly developed IUI is a preference-based measure for urinary problems related to NDO that provides general population-based utility scores with adequate predictive validity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00461292, NCT00311376. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12955-014-0147-7) contains supplementary material, which is available to authorized users

Evaluation of the Measurement Properties of the Short Form 36 Version 2 Health Survey in a Sample of Patients with Multiple Sclerosis

Background: In health status assessment, patient-reported outcome (PRO) measures are tools used to elicit important and measurable information from patients to better understand the impact of health conditions on their lives. Such impacts are considered latent constructs, or variables that cannot be observed or measured directly. Instruments intended to assess latent constructs must satisfy certain development, psychometric, and scaling standards through the generation of both qualitative and quantitative evidence to demonstrate the adequacy of its measurement properties. Health-related quality of life (HRQOL), or the subjective perception of health, is a core concept within the field of PROs. The Short Form 36 (SF-36) is one of the most commonly used PROs used to assess health-related quality of life (HRQOL).Objectives: To provide a better understanding of the performance and dimensionality of the SF-36 version 2 in a cross-sectional sample of patients with multiple sclerosis (MS) on an item, subscale, and higher-order factor structure level using different measurement methods grounded in classical test theory (CTT), factor analysis, and item response theory (IRT).Methods: This was a post hoc analysis of a cross-sectional dataset. Patients with MS were recruited to participate in an online survey asking a variety of questions related to their health and treatment seeking behaviors. The SF-36 was one of the questionnaires included in the survey. Items and individual subscales were evaluated using a multi-trait/multi-item correlation matrix to assess item-to-subscale relationships, including item discriminant validity with other subscales. Unidimensionality for select SF-36 subscales was assessed through confirmatory factor analysis (CFA). Internal consistency reliability (Cronbach's alpha) was evaluated for each subscale. Patient-reported disability, depression, and current symptom exacerbation status were evaluated relative to SF-36 subscale scores to assess convergent validity, discriminant validity, and known-groups validity. Higher-order factor models of the SF-36 were tested to evaluate dimensionality of the instrument, including a two-factor second-order factor model, a bifactor model, and a statistical comparison between the bifactor model and its corresponding nested model. Unidimensionality was further evaluated through the use of graded response IRT models. The relative fit of traditional versus discrimination-constrained models was tested using a -2 loglikelihood ratio test, followed by an evaluation of item-level properties for fit (S-X² statistics), local dependence, and further assessment of model parameters (discrimination parameters, location parameters, option response functions, and test information curves). Person location parameters were also estimated to compare scale information to the location of patients along the latent construct. Results: A total of 1,052 respondents completed the survey. Unidimensionality of individual subscales evaluated via CFA all had confirmatory fit indices (CFI)>0.90, butroot mean square error of approximation [RMSEA] values all exceeded 0.08. All IRT graded response models showed a statistically significant improvement in model fit when item discrimination was freely estimated. Each subscale from the IRT models had at least one mis-fitting item across all unidimensional scales tested (S-X² p-value>0.05), and nearly all subscales tested showed item pairs with signs of local dependence. Cronbach's alpha was>0.80 for all subscales except for General Health [GH] (alpha = 0.78). SF-36 subscales most closely related to physical aspects of health status had the strongest relationship to disability status (physical functioning [PF], r = -0.82, and role physical [RP], r = -0.57). Subscales more closely related to mental health had the largest effect sizes between patients with versus without depression (0.88 for mental health [MH] subscale) and the smallest effect sizes between patients reporting currently experiencing versus not experiencing an exacerbation of their symptoms (0.48 for role emotional [RE]subscale). Both CFA and IRT analyses showed lack of compelling evidence supporting unidimensionality upon combining items from the PF, RP, bodily pain [BP], and GH subscales to form the Physical-21, and upon combining items from the VT, role emotional (RE), social functioning (SF), and MH subscales to form the Mental-14. Higher-order factor models showed good model fit, with CFI>0.90 in all cases and lower RMSEA values than seen for the individual subscales (0.077 to 0.107). The bifactor model fit significantly better than its nested second-order version, however, the best-fitting (i.e., highest CFI and lowest RMSEA) higher-order factor model was the preliminary first-order model with eight first-order factors consistent with the eight subscales of the SF-36 (CFI=0.996, RMSEA=0.077, X² = 3872.14, p<0.001). Conclusions: The SF-36 version 2 performed well when evaluated within the CTT framework, but both CFA and IRT methods revealed several limitations at the item and factor level across all subscales, due to item wording (i.e., positive versus negative), items not being sufficiently related to its latent construct, and local dependence of items within and across subscales. The appropriateness of equal weighting of responses to produce a single summary score for each subscale, as well as their further aggregation into the Physical Component Summary and Mental Component Summary scores should be reevaluated.Release after 31-Dec-202

iASPP/p63 autoregulatory feedback loop is required for the homeostasis of stratified epithelia

iASPP, an inhibitory member of the ASPP (apoptosis stimulating protein of p53) family, is an evolutionarily conserved inhibitor of p53 which is frequently upregulated in human cancers. However, little is known about the role of iASPP under physiological conditions. Here, we report that iASPP is a critical regulator of epithelial development. We demonstrate a novel autoregulatory feedback loop which controls crucial physiological activities by linking iASPP to p63, via two previously unreported microRNAs, miR-574-3p and miR-720. By investigating its function in stratified epithelia, we show that iASPP participates in the p63-mediated epithelial integrity program by regulating the expression of genes essential for cell adhesion. Silencing of iASPP in keratinocytes by RNA interference promotes and accelerates a differentiation pathway, which also affects and slowdown cellular proliferation. Taken together, these data reveal iASPP as a key regulator of epithelial homeostasis