A comparison of the multilevel MIMIC model to the multilevel regression and mixed ANOVA model for the estimation and testing of a cross-level interaction effect: A simulation study

When observing data on a patient-reported outcome measure in, for example, clinical trials, the variables observed are often correlated and intended to measure a latent variable. In addition, such data are also often characterized by a hierarchical structure, meaning that the outcome is repeatedly measured within patients. To analyze such data, it is important to use an appropriate statistical model, such as structural equation modeling (SEM). However, researchers may rely on simpler statistical models that are applied to an aggregated data structure. For example, correlated variables are combined into one sum score that approximates a latent variable. This may have implications when, for example, the sum score consists of indicators that relate differently to the latent variable being measured. This study compares three models that can be applied to analyze such data: the multilevel multiple indicators multiple causes (ML-MIMIC) model, a univariate multilevel model, and a mixed analysis of variance (ANOVA) model. The focus is on the estimation of a cross-level interaction effect that presents the difference over time on the patient-reported outcome between two treatment groups. The ML-MIMIC model is an SEM-type model that considers the relationship between the indicators and the latent variable in a multilevel setting, whereas the univariate multilevel and mixed ANOVA model rely on sum scores to approximate the latent variable. In addition, the mixed ANOVA model uses aggregated second-level means as outcome. This study showed that the ML-MIMIC model produced unbiased cross-level interaction effect estimates when the relationships between the indicators and the latent variable being measured varied across indicators. In contrast, under similar conditions, the univariate multilevel and mixed ANOVA model underestimated the cross-level interaction effect

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A randomized multicenter study of the outcome of brachial-basilic arteriovenous fistula and prosthetic brachial-antecubital forearm loop as vascular access for hemodialysis

BackgroundVascular access is a necessity for patients with end-stage renal disease who need chronic intermittent hemodialysis. According to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, radial-cephalic (RC) and brachial-cephalic (BC) arteriovenous fistulas (AVF) are the first and second choice for vascular access, respectively. If these options are not possible, an autogenous brachial-basilic fistula in the upper arm (BBAVF) or a prosthetic brachial-antecubital forearm loop (PTFE loop) may be considered. Until now, it was not clear which access type was preferable. We have performed a randomized study comparing BBAVF and prosthetic implantation in patients without the possibility for RCAVF or BCAVF.MethodsPatients with failed primary/secondary access or inadequate arterial and/or venous vessels were randomized for either BBAVF or PTFE loop creation. The numbers of complications and interventions were recorded. Kaplan-Meier method was used to calculate primary, assisted-primary and secondary patency rates. The patency rates were compared with the log-rank test. Complication and intervention rates were compared with the Mann-Whitney test.ResultsA total of 105 patients were randomized for a BBAVF or PTFE loop (52 vs 53, respectively). Primary and assisted-primary 1-year patency rates were significantly higher in the BBAVF group: 46% ± 7.4% vs 22% ± 6.1% (P = .005) and 87% ± 5.0% vs 71% ± 6.7% (P = .045) for the BBAVF and PTFE group, respectively. Secondary patencies were comparable for both groups; 89% ± 4.6% vs 85% ± 5.2% for the BBAVF and PTFE group, respectively. The incidence rate of complications was 1.6 per patient-year in the BBAVF group vs 2.7 per patient-year in the PTFE group. Patients in the BBAVF group needed a total of 1.7 interventions per patient-year vs 2.7 per patient-year for the PTFE group.ConclusionThese data show a significantly better primary and assisted-primary patency in the BBAVF group compared with the PTFE group. Furthermore, in the BBAVF group, fewer interventions were needed. Therefore, we conclude that BBAVF is the preferred choice for vascular access if RCAVF or BCAVF creation is impossible, or when these types of access have already failed

Visualization of Coronary Wall Atherosclerosis in Asymptomatic Subjects and Patients with Coronary Artery Disease Using Magnetic Resonance Imaging

Background: Magnetic resonance imaging (MRI) is sensitive to early atherosclerotic changes such as positive remodeling in patients with coronary artery disease (CAD). We assessed prevalence, quality, and extent of coronary atherosclerosis in a group of healthy subjects compared to patients with confirmed CAD. Methodology: Twenty-two patients with confirmed CAD (15M, 7F, mean age 60.4±10.4 years) and 26 healthy subjects without history of CAD (11M, 15F, mean age 56.1±4.4 years) underwent MRI of the right coronary artery (RCA) and vessel wall (MR-CVW) on a clinical 1.5T MR-scanner. Wall thickness measurements of both groups were compared. Principal Findings: Stenoses of the RCA (both < and ≥50% on CAG) were present in all patients. In 21/22 patients, stenoses detected at MRI corresponded to stenoses detected with conventional angiography. In 19/26 asymptomatic subjects, there was visible luminal narrowing in the MR luminography images. Fourteen of these subjects demonstrated corresponding increase in vessel wall thickness. In 4/26 asymptomatic subjects, vessel wall thickening without luminal narrowing was present. Maximum and mean wall thicknesses in patients were significantly higher (2.16 vs 1.92 mm, and 1.38 vs 1.22 mm, both p<0.05). Conclusions: In this cohort of middle-aged individuals, both patients with stable angina and angiographically proven coronary artery disease, as well as age-matched asymptomatic subjects. exhibited coronary vessel wall thickening detectable with MR coronary vessel wall imaging. Maximum and mean wall thicknesses were significantly higher in patients. The vast majority of asymptomatic subjects had either positive remodeling without luminal narrowing, or non-significant stenosis. Trial registration ClinicalTrials.gov NCT00456950

Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial

INTRODUCTION: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis. METHODS: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed. RESULTS: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most. CONCLUSION: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems.</p

Observational Dutch Young Symptomatic StrokE studY (ODYSSEY): Study rationale and protocol of a multicentre prospective cohort study

Background: The proportion of strokes occurring in younger adults has been rising over the past decade. Due to the far longer life expectancy in the young, stroke in this group has an even larger socio-economic impact. However, information on etiology and prognosis remains scarce.Methods/design: ODYSSEY is a multicentre prospective cohort study on the prognosis and risk factors of patients with a first-ever TIA, ischemic stroke or intracerebral hemorrhage aged 18 to 49 years. Our aim is to include 1500 patients. Primary outcome will be all cause mortality and risk of recurrent vascular events. Secondary outcome will be the risk of post-stroke epilepsy and cognitive impairment. Patients will complete structured questionnaires on outcome measures and risk factors. Both well-documented and less well-documented risk factors and potentially acute trigger factors will be investigated. Patients will be followed every 6 months for at least 3 years. In addition, an extensive neuropsychological assessment will be administered both at baseline and 1 year after the stroke/TIA. Furthermore we will include 250 stroke-free controls, who will complete baseline assessment and one neuropsychological assessment.Discussion: ODYSSEY is designed to prospectively determine prognosis after a young stroke and get more insight into etiology of patients with a TIA, ischemic stroke and intracerebral hemorrhage in patients aged 18 to 49 years old in a large sample size

Efficacy and safety of on-demand use of 2 treatments designed for different etiologies of female sexual interest/arousal disorder:3 Randomized Clinical Trials

Background In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. Aim To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. Methods 497 women (21–70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). Outcomes The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. Results In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57–2.84, P =.004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44–3.45, P =.012; T: Δ = 1.69, 95% CI = 0.58–2.80, P =.003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17–1.82, P =.019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57–2.46, P =.002; T: Δ = 0.98, 95% CI = 0.17–1.78, P =.018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). Clinical Implications T + S and T + B are promising treatments for women with FSIAD. Strengths and Limitations The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. Conclusions T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2018;15:201–216