Event-driven Design Research Articles

Flexible Spline Models for Blinded Sample Size Reestimation in Event-Driven Clinical Trials.

In event-driven trials, the target power under a certain treatment effect is maintained as long as the required number of events is obtained. The misspecification of the survival function in the planning phase does not result in a loss of power. However, the trial might take longer than planned if the event rate is lower than assumed. Blinded sample size reestimation (BSSR) uses non-comparative interim data to adjust the sample size if some planning assumptions are wrong. In the setting of an event-driven trial, the sample size may be adjusted to maintain the chances to obtain the required number of events within the planned time frame. For the purpose of BSSR, the survival function is estimated based on the interim data and often needs to be extrapolated. The current practice is to fit standard parametric models, which may however not always be suitable. Here we propose a flexible spline-based BSSR method. Specifically, we propose to carry out the extrapolation based on the Royston-Parmar spline model. To compare the proposed procedure with parametric approaches, we carried out a simulation study. Although parametric approaches might seriously over- or underestimate the expected number of events, the proposed flexible approach avoided such undesirable behavior. This is also observed in an application to a secondary progressive multiple sclerosis trial. Overall, if planning assumptions are wrong this more robust flexible BSSR method could help event-driven designs to more accurately adjust recruitment numbers and to finish on time.

The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF): Rationale and design.

Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a unique pragmatic registry-based randomized controlled trial. SPIRRIT-HFpEF is a multicentre, prospective, randomized, open-label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N-terminal pro-B-type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre-specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event-driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients. SPIRRIT-HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry-based trials in heart failure and other chronic conditions.

Multi-Modal Trust Architecture for AI-HR Systems: Analyzing Technical Determinants of User Acceptance in Enterprise-Scale People Analytics Platforms

This comprehensive technical paper presents a novel multi-modal trust architecture for AI-driven HR systems, focusing on the critical aspects of user acceptance in enterprise-scale people analytics platforms. Through the implementation of advanced zero-knowledge proof protocols, explainable AI frameworks, blockchain-based audit trails, and federated learning approaches, the architecture achieved an 85% improvement in user confidence metrics. The system demonstrates remarkable performance across resistance prediction, technical integration, and trust analytics, processing over 9.5 million daily interactions with 99.999% reliability. Our implementation across 1,850 organizations showed an 82% enhancement in system trustworthiness and a 2.8x improvement in operational efficiency, while reducing algorithmic bias by 89%. The architecture's event-driven design and microservices implementation resulted in a 76% improvement in system responsiveness and a 92% reduction in data processing latency, establishing a new benchmark for trust-centric AI-HR systems.

Building a Scalable API for Restaurant Online Ordering Systems

The digital transformation of the restaurant industry has made online ordering systems indispensable, enabling convenience for customers and operational efficiency for businesses. This article delves into the pivotal role of scalable APIs (Application Programming Interfaces) in enhancing restaurant operations amidst increasing consumer expectations and technological demands. APIs enable seamless communication between software components, addressing critical challenges such as managing high transaction volumes, integrating online ordering with Point of Sale (POS) systems, providing real-time updates, and ensuring data security. The key features of scalable APIs include real-time inventory synchronization, dynamic menu management, robust error handling, and multi-platform compatibility. These capabilities ensure that restaurants can adapt to high-traffic situations, minimize operational errors, and deliver a unified customer experience. Leveraging modern technologies like microservices architecture, event-driven designs, and programming languages like Go (Golang), APIs facilitate elastic scalability, ensuring operational efficiency even during peak demands. Additionally, the case study of SpotOn demonstrates the tangible benefits of implementing scalable APIs. These include improved transaction handling, seamless system integration, enhanced customer satisfaction, and operational resilience. APIs also support long-term growth by enabling third-party integrations, automating processes, and adapting to emerging technologies such as Artificial Intelligence (AI) and the Internet of Things (IoT). As the industry evolves, scalable APIs will be instrumental in driving innovation, meeting consumer demands, and fostering sustainable growth. This article positions APIs as not just technical enablers but strategic assets essential for restaurants aiming to thrive in a rapidly digitizing and competitive market.

Abstract OT2-12-03: Pivotal study of the Lum imaging system for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer: The INCITE trial

Abstract Background Breast-conserving surgery is a critical step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to guide in real-time the removal of cancer missed during the initial lumpectomy to reduce the number of second operations. The pegulicianine imaging agent is injected intravenously before surgery and its fluorescence signal is activated by proteases in tumor cells and cells at the tumor margin. The LUM Imaging System visualizes activated pegulicianine in the lumpectomy cavity via a hand-held detector and proprietary tumor detection software. This system was previously tested in multiple single-site studies and a prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design and Specific Aims: The current prospective, multi-center, randomized, blinded study was designed to show the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to demonstrate guided removal of residual cancer in the lumpectomy missed during the initial procedure and potentially reduce the rates of positive margins. This study is powered by an event-driven design that requires 70 truth-standard positive events. It is expected that approximately 390 women at fourteen medical centers across the US will be enrolled to achieve the number of events. Pegulicianine is injected 2-6 hours prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy followed by blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in regions where SOC shaves will be taken. The patient is then randomized. If the random assignment is to the device arm, the surgeon is directed to excise margins that have positive LUM signal. Pathologists are blinded to the source of tissue removed (SOC vs. LUM) when conducting the pathology assessment. The amount of additional tissue volume resected is also evaluated. Patient reported outcome data is collected as a quality-of-life survey before and after the subject’s lumpectomy.Eligibility Criteria: This study seeks to enroll women with primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. Patients must not have a history of allergic reaction to polyethylene glycol, contrast agents, or have received neoadjuvant therapy to treat their current breast cancer. Use of blue dyes before imaging with the LUM System are not allowed. Additional detailed eligibility criteria are listed in the protocol. Accrual and Study Progress To date, 350 subjects have participated in this trial. This study is funded in part by the National Cancer Institute (5R44CA211013). This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Irene Wapnir, Donna Dyess, Shelly Hwang, Nayana Dekhne, Daleela Dodge, Beth-Ann Lesnikoski, Kelly Hunt, Patricia Clark, Stephanie Valente, Marie Catherine Lee, Lynne Clark, Brian Schlossberg, Sean Madden, Alejandra Rodriguez, Kate Smith, Manna Chang, Barbara Smith. Pivotal study of the Lum imaging system for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer: The INCITE trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-12-03.

Abstract CT259: Pivotal Study of the LUM Imaging System for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer

Abstract Background Breast-conserving surgery is a critical first step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% or more of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to identify residual cancer in real time during the initial lumpectomy to reduce the number of second operations. LUM015 is a protease-activated fluorescent imaging agent that accumulates in tumor cells and tumor associated macrophages. The LUM Imaging System camera visualizes the intravenously injected LUM015 in the lumpectomy cavity via a hand-held wide field detector and proprietary tumor detection software. This imaging system was previously tested in multiple single-site studies and a large, prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design The current prospective, multi-center, randomized, blinded study was designed to demonstrate the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to identify residual cancer in the lumpectomy cavity to reduce the rates of positive margins. This study seeks to enroll women with primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. Approximately 310 women at 14 US medical centers will be enrolled. This study is powered by an event-driven design that requires 70 patients to be enrolled that have a ‘truth-standard positive' event, which is the identification of cancer in a protocol defined tissue type. To be eligible, patients must not have a history of allergic reaction to polyethylene glycol, intravenous contrast agents, or systemic therapies to treat their cancer. Use of blue dyes before imaging with the LUM System are not allowed. LUM015 is injected prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy and perform blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in regions where SOC shaves will be taken. The patient is then randomized. If the random assignment is to the device arm, the surgeon is directed to excise margins that the LUM System indicates are positive for cancer. Pathologists are blinded to the type of tissue removed when conducting the pathology assessment. Patient reported outcome data is collected as a quality-of-life survey before and after the subject's lumpectomy. Additional detailed eligibility criteria are in the protocol. To date, 166 patients have participated in this trial. This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Irene Wapnir, Donna Dyess, Shelly Hwang, Nayana Dekhne, Daleela Dodge, Beth-Ann Lesnikoski, Kelly Hunt, Patricia Clark, Stephanie Valente, M. Catherine Lee, Lynne Clark, Brian Schlossberg, Sean Madden, Alejandra Rodriguez, Kate Smith, Manna Chang, Barbara Smith. Pivotal Study of the LUM Imaging System for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT259.

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial

Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Novartis Pharma.

Event-driven Modelling Method for Sub-assembly Intelligent Production Line

Focusing on the design of sub-assemble intelligent production line, an event-driven design method for production line was proposed. With the method, the manufacturing activity was defined as event, and then the relationships among events are analysed to define the input-output and execution behaviours digitally in each stage. Furthermore, the event-driven execution mechanism for multi-stage process was built to describe the production line in digital. The digital model of production line was conducted to explore the event behaviours, which will support the research about data-driven production line simulation in future work.

Design and rationale of the TOTAL trial: A randomized trial of routine aspiration ThrOmbecTomy with percutaneous coronary intervention (PCI) versus PCI ALone in patients with ST-elevation myocardial infarction undergoing primary PCI

A major limitation of primary percutaneous coronary intervention (PPCI) for the treatment of ST-elevation myocardial infarction (STEMI) is impaired microvascular perfusion due to embolization and obstruction of microcirculation with thrombus. Manual thrombectomy has the potential to reduce distal embolization and improve microvascular perfusion. Clinical trials have shown mixed results regarding thrombectomy. The objective of this study is to evaluate the efficacy of routine upfront manual aspiration thrombectomy during PPCI compared with percutaneous coronary intervention alone in patients with STEMI. This is a multicenter, prospective, open, international, randomized trial with blinded assessment of outcomes. Patients with STEMI undergoing PPCI are randomized to upfront routine manual aspiration thrombectomy with the Export catheter (Medtronic CardioVascular, Santa Rosa, CA) or to percutaneous coronary intervention alone. The primary outcome is the composite of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or new or worsening New York Heart Association class IV heart failure up to 180 days. The trial uses an event-driven design and will recruit 10,700 patients. The TOTAL trial will determine the effect of routine manual aspiration thrombectomy during PPCI on clinically important outcomes.

CrossQuery: A Web Tool for Easy Associative Querying of Transcriptome Data

Enormous amounts of data are being generated by modern methods such as transcriptome or exome sequencing and microarray profiling. Primary analyses such as quality control, normalization, statistics and mapping are highly complex and need to be performed by specialists. Thereafter, results are handed back to biomedical researchers, who are then confronted with complicated data lists. For rather simple tasks like data filtering, sorting and cross-association there is a need for new tools which can be used by non-specialists. Here, we describe CrossQuery, a web tool that enables straight forward, simple syntax queries to be executed on transcriptome sequencing and microarray datasets. We provide deep-sequencing data sets of stem cell lines derived from the model fish Medaka and microarray data of human endothelial cells. In the example datasets provided, mRNA expression levels, gene, transcript and sample identification numbers, GO-terms and gene descriptions can be freely correlated, filtered and sorted. Queries can be saved for later reuse and results can be exported to standard formats that allow copy-and-paste to all widespread data visualization tools such as Microsoft Excel. CrossQuery enables researchers to quickly and freely work with transcriptome and microarray data sets requiring only minimal computer skills. Furthermore, CrossQuery allows growing association of multiple datasets as long as at least one common point of correlated information, such as transcript identification numbers or GO-terms, is shared between samples. For advanced users, the object-oriented plug-in and event-driven code design of both server-side and client-side scripts allow easy addition of new features, data sources and data types.

Distributed Event-Based Systems: An Emerging Community

Events and messaging have been in use in industry for years. With the advent of service-oriented and event-driven architectures, however, the eventing paradigm becomes a central building block of business IT. Event-based techniques have established themselves as an efficient way to structure such systems and handle challenging interaction patterns between components. Event-driven design offers the flexibility to address these issues and reflects the real world's event-driven nature

Confidentiality Issues within a Clinical Information System: Moving from Data-driven to Event-driven Design

Within a hospital, the moving of medical information systems from retrospective data-gathering methods to prospective clinical information systems raises the question of the confidentiality of patient data. A method of improving the traditional matrix model usually used to achieve access controls is described. The event-driven model refers to the way a security system ensures that a given user has a valid "need-to" relationship to a given patient. Events are defined as the occurrence of specific data that trigger the creation or the updating of the relationship between the identity of a user and the identity of a patient (e.g., admission, discharge, transfer, prescription, and report). The creation and the deletion of the relationships between users and patients are based on numerous repositories and working lists of patients. This implementation requires an organization of the hospital activities which is able to manage, in a real-time manner, those repositories as closely as possible to the steps occurring during the patient's care process. Although this approach seems to reasonably fit the dynamic of the care process, it adds significant organizational constraints.

TITAC: design of a quasi-delay-insensitive microprocessor

TITAC is an asynchronous version of an 8-bit von Neumann microprocessor based on the delay-insensitive model incorporating the isochronic-forks assumption. In its two-phase, event-driven design scheme, a working phase and an idle phase alternate to execute control and data transfer. The data path design uses a two-rail, multilevel AND-OR scheme with a binary decision diagram structure for efficient signal generation. >