There is a growing recognition of the importance to involve patients in every stage of drug development. This shift acknowledges that patients' perspectives, experiences, and preferences are essential for ensuring that treatments meet real-world needs. In this context, a new body of statistical literature has emerged, focusing not only on the simultaneous consideration of multiple outcomes that reflect patients' overall experiences, but also on their structured prioritization. We refer to this class of approaches as hierarchical multi-component statistical methods. Among these, two influential frameworks - generalized pairwise comparisons (GPC) and desirability of outcome ranking (DOOR) - have emerged in the last decade, each aiming to offer a comprehensive approach to evaluating treatment effects. A new methodology, referred to here as the Markov ordinal state transition model (MOST), has recently been introduced without focusing on an explicit link with GPC nor DOOR. This paper seeks to fill this gap by offering a comprehensive and comparative analysis of the three approaches. Through examples and an exploration of the structural and philosophical differences between the methods, our aim is to provide guidance and encourage lines of research in the rapidly-evolving landscape of hierarchical multi-component statistical methodologies.

OBJECTIVE:Dravet syndrome (DS) is a rare genetic developmental and epileptic encephalopathy syndrome characterized by refractory seizures and neurodevelopmental disorders beginning in infancy. This study aims to understand the natural history of DS by utilizing longitudinal data from patient registries. METHODS:We analysed data from 475 subjects across two European patient registries (RESIDRAS and Platform-RESIDRAS) from Dravet Italia Onlus, collected between 2010 and 2024. The study included only participants that were under 18 years old. Clinical characteristics such as seizure types and speech development were modelled using generalized linear mixed models and ordinal transition models. RESULTS:Unilateral seizures predominantly occurred during infancy and early childhood, while generalized convulsive and focal to bilateral tonic-clonic seizures increased with age, showing a higher incidence in boys. Focal seizures peaked around the age of three years before declining. Speech development varied, with most participants initially having poor speech. However, a considerable number of transitions between different levels of speech impairment were observed over time. Transition models indicated that once speech is acquired, the likelihood of losing this ability is negligible. SIGNIFICANCE:Patient registries are instrumental in modelling the disease history of DS, offering insight into its progression by means of advanced statistical modelling techniques that build on clinical expertise. Future research should focus on evaluating the effects of therapies and exploring the interrelations between different clinical characteristics. Understanding these aspects can guide better management strategies and improve patient outcomes.

Aims Trials on integrated care for atrial fibrillation (AF) showed mixed results in different AF populations using various approaches. The multicentre, randomized AF-EduCare trial evaluated the effect of targeted patient education on unplanned cardiovascular outcomes. Methods and results Patients willing to participate were randomly assigned to in-person education, online education, or standard care (SC) and followed for minimum 18 months. Education focused on four aspects of integrated AF care: (i) knowledge on AF and oral anticoagulation; (ii) reinforcement of medication adherence; (iii) awareness about risk factors; and (iv) reachability for AF-related questions. The primary endpoint was the composite of cumulative events of unplanned cardiovascular hospitalizations and consultations, emergency department visits for cardiovascular reasons, and cardiovascular death. A total of 1038 patients (69.8 +/- 9.2 years) were followed up for 26.9 +/- 9.4 months. Education (both in-person and online) significantly improved AF-related knowledge compared to SC (P < 0.001), increased patient awareness about risk factors, led to high medication adherence, and encouraged patients to ask health-related questions. However, in-person education did not show an effect on the primary outcome compared to SC [HR 1.02 (0.91-1.14); P = 0.80] that was also not the case when comparing online education vs. SC [HR 1.18 (0.95-1.46), P = 0.65]. Exploratory subgroup analyses showed a heterogeneous effect over the centres, but a positive impact of in-person education in patients with asymptomatic AF, being 70 years old or younger, and without a history of heart failure. Conclusion AF-EduCare showed that intensive targeted patient education did not lead to less unplanned cardiovascular events in the AF patient population as a whole, although subgroups might benefit.

BACKGROUND:Patients with unexplained dyspnea and an elevated mean pulmonary artery pressure (mPAP)/cardiac output (CO) slope on invasive hemodynamic assessment during exercise have worse clinical outcomes. The aim of this study was to evaluate the incremental prognostic value of the noninvasive mPAP/CO slope in addition to heart failure with preserved ejection fraction (HFpEF) probability scores and diastolic stress testing in patients with unexplained dyspnea. METHODS:In a multicenter cohort study involving six Belgian dyspnea clinics, patients with unexplained dyspnea underwent exercise echocardiography for mPAP/CO slope assessment. Positive HFpEF scores were defined as HFA-PEFF (Heart Failure Association pretest probability echocardiography, functional testing, final diagnosis) score ≥ 5 and H2FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder, filling pressure) score ≥ 6. The outcome evaluated was a composite of all-cause mortality or heart failure hospitalization. RESULTS:Among 2,452 patients (mean age, 63 ± 15 years; 53% women), mPAP/CO slope > 3.5 mm Hg · L-1 · min-1 best predicted adverse outcomes. The prognostic value of the mPAP/CO slope was greater in patients with negative HFpEF scores than in those with positive scores (interaction P = .02). The mPAP/CO slope remained independently prognostic after adjustment for N-terminal pro-B-type natriuretic peptide (hazard ratio [HR], 2.26; 95% CI, 1.33-3.82) and for HFpEF scores and diastolic stress testing (HR, 1.99; 95% CI, 1.37-2.88), whereas exercise tricuspid regurgitant velocity did not. Both HFpEF score-negative patients with slope > 3.5 mm Hg · L-1 · min-1 (HR, 2.99; 95% CI, 1.81-4.95) and HFpEF score-positive patients (HR, 6.29; 95% CI, 4.25-9.31) showed significantly higher risk compared with HFpEF score-negative patients with slope ≤ 3.5 mm Hg · L-1 · min-1. CONCLUSIONS:The mPAP/CO slope, unlike exercise tricuspid regurgitant velocity, adds prognostic value beyond natriuretic peptides, HFpEF scores, and diastolic stress testing, identifying high-risk patients with exercise-induced hemodynamic abnormalities who may benefit from invasive confirmation and closer follow-up.

BACKGROUND:Several COVID-19 vaccines have been licensed. To support the assessment of safety signals, we developed a toolkit to support COVID-19 vaccine monitoring and benefit-risk assessment. We aim to show the application of our toolkit in the EU using thrombosis with thrombocytopenia syndrome (TTS) associated with the Vaxzevria (AstraZeneca) vaccine as a use case. METHODS:In this population-based study, we used a model incorporating data from multiple EU sources such as The European Surveillance System and EudraVigilance, and estimated the benefits of COVID-19 vaccines by comparing the observed COVID-19 confirmed cases, hospitalisations, intensive care unit (ICU) admissions, and deaths across Europe to the expected numbers in the absence of Vaxzevria vaccination. Risks of TTS associated with Vaxzevria were calculated by comparing the observed number of TTS events in individuals who received Vaxzevria to the expected number of events based on background incidence rates. To visualise the results, we developed a toolkit with an interactive web application. FINDINGS:62 598 505 Vaxzevria vaccines (32 763 183 to females and 29 835 322 to males) had been administered in Europe by Feb 10, 2021. Our results showed that a first dose of Vaxzevria provided benefits across all age groups. Based on vaccine effectiveness estimates and reported coverage in Europe, from Dec 13, 2020 to Dec 31, 2021, vaccination with Vaxzevria was estimated to prevent (per 100 000 doses) 12 113 COVID-19 cases, 1140 hospitalisations, 184 ICU admissions, and 261 deaths. Women aged 30-59 years and males aged 20-29 years had the highest frequency of TTS events. The benefits of vaccination outweighed the risks of TTS in all age groups, with the highest benefits and risks observed in individuals aged 60-69 years. INTERPRETATION:Our toolkit and underlying model contextualised the risk of TTS associated with Vaxzevria relative to its benefits. The methodology employed could be applied to other serious adverse events related to COVID-19 or other vaccines. The adaptability and versatility of such toolkits might contribute to strengthening preparedness for future public health emergencies. FUNDING:European Medicines Agency.

Rare diseases present critical challenges to healthcare systems, patients, and caregivers due to their low prevalence and unique characteristics. Designing clinical trials and developing statistical methodologies for evaluating interventions in rare diseases face several challenges. The “EBStatMax” project, part of the European Joint Programme on Rare Diseases’ Demonstration Projects, aimed to address one of these challenges, namely: designing and analyzing longitudinal cross-over data in rare diseases, like Epidermolysis bullosa simplex (EBS). Although the main findings of the project have been published elsewhere, this manuscript reflects on additional hurdles encountered during the project, particularly regarding outcomes and methodological considerations. It explores issues surrounding outcome measurement, statistical methodology, and clinical considerations, emphasizing their broader relevance to methodological advancements in rare disease research beyond this specific case. This manuscript highlights the critical role of international collaboration in rare disease research to enhance evidence quality and aims to inspire further advancements in the field.

Journal Article Accepted manuscript From Non-Inferiority to Superiority: The Shift Toward Patient-Centric Outcomes Get access Johan Verbeeck, Johan Verbeeck DSI, I-Biostat, University Hasselt, Hasselt, Belgium [email protected] https://orcid.org/0000-0002-4923-1032 Search for other works by this author on: Oxford Academic Google Scholar Mickaël De Backer, Mickaël De Backer UCB, Brussels, Belgium Search for other works by this author on: Oxford Academic Google Scholar Marc Buyse Marc Buyse IDDI, Louvain-la-Neuve, Belgium https://orcid.org/0000-0002-4559-0994 Search for other works by this author on: Oxford Academic Google Scholar European Heart Journal. Acute Cardiovascular Care, zuaf004, https://doi.org/10.1093/ehjacc/zuaf004 Published: 11 January 2025 Article history Received: 07 January 2025 Accepted: 07 January 2025 Published: 11 January 2025

Amid the global COVID-19 pandemic, vaccines were conditionally authorized for human use to protect against severe infection. The Benefit Risk Assessment of VaccinEs (BRAVE) toolkit, a user-friendly R Shiny application, was developed retrospectively together with the European Medicine Agency (EMA) with the aim of fulfilling the need for flexible tools to assess vaccine benefits and risks during and outside a pandemic situation. This study employed BRAVE to evaluate the impact of COVID-19 mRNA vaccines across 30 European Union (EU)/EEA countries by quantifying the number of prevented clinical events [i.e. confirmed infections, hospitalizations, intensive care unit (ICU) admissions, and deaths], using a probabilistic model informed by real-time incidence data and vaccine effectiveness estimates. The analysis assumes fixed population dynamics and behaviour. Additionally, BRAVE assesses risks associated with mRNA-based vaccines (myocarditis or pericarditis) by comparing observed incidence rates in vaccinated individuals with background incidence rates. mRNA vaccines were estimated to directly prevent 11.150 million [95% confidence interval (CI): 10.876-11.345] confirmed COVID-19 infections, 0.739 million (95% CI: 0.727-0.744) COVID-19 hospitalizations, 0.107 million (95% CI: 0.104-0.109) ICU admissions, and 0.187 million (95% CI: 0.182-0.189) COVID-19-related deaths in the EU/EEA between 13 December 2020 and 31 December 2021. Despite increased vaccination-associated myocarditis or pericarditis observed in younger men, the benefits of vaccination still outweigh these risks. Our study supports the benefit/risk profile of COVID-19 vaccines and emphasizes the utility of employing a flexible toolkit to assess risks and benefits of vaccination. This user-friendly and adaptable toolkit can serve as a blueprint for similar tools, enhancing preparedness for future public health crises.

In clinical trials, the primary objective often involves studying the associations between several variables.In randomized clinical trials (RCTs), the focus typically lies on the association between clinical outcomes and two or several treatment options.Conversely, in observational studies, interest extends beyond

Abstract Introduction COVID-19 caused a high burden of sick leave worldwide. Long-term sick leave for COVID-19 may be longer than for other influenza-like syndromes. The real impact of COVID on absenteeism remains uncertain. The aim of our study was to investigate the burden of sick leave, especially > 12 weeks, in Belgian workers with a positive PCR test for SARS-CoV-2 from July 2020 to September 2021 and to compare these figures with sick leave for other infectious diseases. Methods We coupled a database of SARS-CoV-2–positive workers and workers who were absent for other infections with objective absence data. Predictors of prolonged sickness were evaluated by negative binomial regression, Cox proportional-hazards regression and ordinal logistic regression. Results The study population involved 2569 workers who tested positive for SARS-CoV-2 and 392 workers who were absent for other infectious diseases. In total, 16% (95%CI: 14-17%) of workers with a positive SARS-CoV-2 test had no sick leave registered. The prevalence of long-term sick leave was 1.39% (95%CI: 0.94-1.97) in workers with COVID-19 and 4.34% (95%CI: 2.55-6.85) in workers with other infectious diseases. When including PCR-positive workers without sick leave, the prevalence of long-term sick leave decreased to 1.17% (95%CI: 0.79-1.66). Long sick leave was associated with older age, high previous sick leave and low educational level. Discussion and conclusion The prevalence of long-term sick leave was lower than estimated in earlier investigations, regardless of worrying reports about post-COVID-19 syndrome.

Epidermolysis bullosa simplex (EBS) skin disease is a rare disease, which renders the use of optimal design techniques especially important to maximize the potential information in a future study, that is, to make efficient use of the limited number of available subjects and observations. A generalized linear mixed effects model (GLMM), built on an EBS trial was used to optimize the design. The model assumed a full treatment effect in the follow-up period. In addition to this model, two models with either no assumed treatment effect or a linearly declining treatment effect in the follow-up were assumed. The information gain and loss when changing the number of EBS blisters counts, altering the duration of the treatment as well as changing the study period was assessed. In addition, optimization of the EBS blister assessment times was performed. The optimization was utilizing the derived Fisher information matrix for the GLMM with EBS blister counts and the information gain and loss was quantified by D-optimal efficiency. The optimization results indicated that using optimal assessment times increases the information of about 110-120%, varying slightly between the assumed treatment models. In addition, the result showed that the assessment times were also sensitive to be moved ± one week, but assessment times within ± two days were not decreasing the information as long as three assessments (out of four assessments in the trial period) were within the treatment period and not in the follow-up period. Increasing the number of assessments to six or five per trial period increased the information to 130% and 115%, respectively, while decreasing the number of assessments to two or three, decreased the information to 50% and 80%, respectively. Increasing the length of the trial period had a minor impact on the information, while increasing the treatment period by two and four weeks had a larger impact, 120% and 130%, respectively. To conclude, general applications of optimal design methodology, derivation of the Fisher information matrix for GLMM with count data and examples on how optimal design could be used when designing trials for treatment of the EBS disease is presented. The methodology is also of interest for study designs where maximizing the information is essential. Therefore, a general applied research guidance for using optimal design is also provided.

BACKGROUND:Across Europe, countries have responded to the COVID-19 pandemic with a combination of non-pharmaceutical interventions and vaccination. Evaluating the effectiveness of such interventions is of particular relevance to policy-makers. METHODS:We leverage almost three years of available data across 38 European countries to evaluate the effectiveness of governmental responses in controlling the pandemic. We developed a Bayesian hierarchical model that flexibly relates daily COVID-19 incidence to past levels of vaccination and non-pharmaceutical interventions as summarised in the Stringency Index. Specifically, we use a distributed lag approach to temporally weight past intervention values, a tensor-product smooth to capture non-linearities and interactions between both types of interventions, and a hierarchical approach to parsimoniously address heterogeneity across countries. RESULTS:We identify a pronounced negative association between daily incidence and the strength of non-pharmaceutical interventions, along with substantial heterogeneity in effectiveness among European countries. Similarly, we observe a strong but more consistent negative association with vaccination levels. Our results show that non-linear interactions shape the effectiveness of interventions, with non-pharmaceutical interventions becoming less effective under high vaccination levels. Finally, our results indicate that the effects of interventions on daily incidence are most pronounced at a lag of 14 days after being in place. CONCLUSIONS:Our Bayesian hierarchical modelling approach reveals clear negative and lagged effects of non-pharmaceutical interventions and vaccination on confirmed COVID-19 cases across European countries.