scholarly journals A mathematical framework to quantify the masking effect associated with the confidence intervals of measures of disproportionality

2017 ◽  
Vol 8 (7) ◽  
pp. 231-244 ◽  
Author(s):  
François Maignen ◽  
Manfred Hauben ◽  
Jean-Michel Dogné
Keyword(s):  
Confidence Interval ◽  
Proportional Reporting Ratio ◽  
Primary Objective ◽  
Masking Effect ◽  
Drug Event ◽  
Mathematical Framework ◽  
True Positive ◽  
Event Pair ◽  
Mathematical Relation ◽  
Statistical Issue

Background: The lower bound of the 95% confidence interval of measures of disproportionality (Lower95CI) is widely used in signal detection. Masking is a statistical issue by which true signals of disproportionate reporting are hidden by the presence of other medicines. The primary objective of our study is to develop and validate a mathematical framework for assessing the masking effect of Lower95CI. Methods: We have developed our new algorithm based on the masking ratio (MR) developed for the measures of disproportionality. A MR for the Lower95CI (MRCI) is proposed. A simulation study to validate this algorithm was also conducted. Results: We have established the existence of a very close mathematical relation between MR and MRCI. For a given drug–event pair, the same product will be responsible for the highest masking effect with the measure of disproportionality and its Lower95CI. The extent of masking is likely to be very similar across the two methods. An important proportion of identical drug–event associations affected by the presence of an important masking effect is revealed by the unmasking exercise, whether the proportional reporting ratio (PRR) or its confidence interval are used. Conclusion: The detection of the masking effect of Lower95CI can be automated. The real benefits of this unmasking in terms of new true-positive signals (rate of true-positive/false-positive) or time gained by the revealing of signals using this method have not been fully assessed. These benefits should be demonstrated in the context of prospective studies.

scholarly journals Using ActionADE to create information continuity to reduce re-exposures to harmful medications: study protocol for a randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jeffrey P. Hau ◽  
Penelope M. A. Brasher ◽  
Amber Cragg ◽  
Serena Small ◽  
Maeve Wickham ◽  
...  
Keyword(s):  
Health Information ◽  
Adverse Drug Event ◽  
Primary Outcome ◽  
Adverse Drug Events ◽  
Primary Objective ◽  
Drug Event ◽  
Controlled Trials ◽  
Drug Reactions ◽  
Main Trial ◽  
Randomized Controlled

Abstract Background Repeat exposures to culprit medications are a common cause of preventable adverse drug events. Health information technologies have the potential to reduce repeat adverse drug events by improving information continuity. However, they rarely interoperate to ensure providers can view adverse drug events documented in other systems. We designed ActionADE to enable rapid documentation of adverse drug events and communication of standardized information across health sectors by integrating with legacy systems. We will leverage ActionADE’s implementation to conduct two parallel, randomized trials: patients with adverse drug reactions in the main trial and those diagnosed with non-adherence in a secondary trial. Primary objective of the main trial is to evaluate the effects of providing information continuity about adverse drug reactions on culprit medication re-dispensations over 12 months. Primary objective of the secondary trial is to evaluate the effect of providing information continuity on adherence over 12 months. Methods We will conduct two parallel group, triple-blind randomized controlled trials in participating hospitals in British Columbia, Canada. We will enroll adults presenting to hospital with an adverse drug event to prescribed outpatient medication. Clinicians will document the adverse drug event in ActionADE. The software will use an algorithm to determine patient eligibility and allocate eligible patients to experimental or control. In the experimental arm, ActionADE will transmit information to PharmaNet, where adverse drug event information will be displayed in community pharmacies when re-dispensations are attempted. In the control arm, ActionADE will retain information in the local record. We will enroll 3600 adults with an adverse drug reaction into the main trial. The main trial’s primary outcome is re-dispensation of a culprit or same-class medication within 12 months; the secondary trial’s primary outcome will be adherence to culprit medication. Secondary outcomes include health services utilization and mortality. Discussion These studies have the potential to guide policy decisions and investments needed to drive health information technology integrations to prevent repeat adverse drug events. We present an example of how a health information technology implementation can be leveraged to conduct pragmatic randomized controlled trials. Trial registration ClinicalTrials.gov NCT04568668, NCT04574648. Registered on 1 October 2020.

Adverse Drug Events in the Prevention and Treatment of COVID-19: A Data Mining Study on FDA Adverse Event Reporting System (FAERS) (Preprint)

2021 ◽  
Author(s):  
Qiang Guo ◽  
Shaojun Duan ◽  
Yaxi Liu ◽  
Yinxia Yuan
Keyword(s):  
Data Mining ◽  
Adverse Event ◽  
Adverse Drug Events ◽  
Reporting System ◽  
Proportional Reporting Ratio ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Drug Event ◽  
Event Reporting ◽  
Prevention And Treatment

BACKGROUND In the emergency situation of COVID-19, off-label therapies and newly developed vaccines may bring the patients adverse drug event (ADE) risks. Data mining based on spontaneous reporting systems (SRSs) is a promising and efficient way to detect potential ADEs so as to help health professionals and patients get rid of these risks. OBJECTIVE This pharmacovigilance study aimed to investigate the ADEs of “Hot Drugs” in COVID-19 prevention and treatment based on the data of the US Food and Drug Administration (FDA) adverse event reporting system (FAERS). METHODS FAERS ADE reports associated with COVID-19 from the 2nd quarter of 2020 to the 2nd quarter of 2021 were retrieved with “Hot Drugs” and frequent ADEs recognized. A combination of support, proportional reporting ratio (PRR) and Chi-square (2) test was applied to detect significant “Hot Drug” & ADE signals by Python programming language on Jupyter notebook. RESULTS 13,178 COVID-19 cases were retrieved with 18 “Hot Drugs” and 312 frequent ADEs on “Preferred Term” (PT) level. 18  312 = 5,616 “Drug & ADE” candidates were formed for further data mining. The algorithm finally produced 219 significant ADE signals associated with 17 “Hot Drugs”and 124 ADEs.Some unexpected ADE signals were observed for chloroquine, ritonavir, tocilizumab, Oxford/AstraZeneca COVID-19 Vaccine and Moderna COVID-19 Vaccine. CONCLUSIONS Data mining is a promising and efficient way to assist pharmacovigilance work and the result of this paper could help timely recognize ADEs in the prevention and treatment of COVID-19.

ENVASARC: A pivotal trial of envafolimab, and envafolimab in combination with ipilimumab, in patients with advanced or metastatic undifferentiated pleomorphic sarcoma or myxofibrosarcoma who have progressed on prior chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11581-TPS11581
Author(s):  
Sandra P. D'Angelo ◽  
Steven Ian Robinson ◽  
Joelle Lam ◽  
Bonne J. Adams ◽  
James L. Freddo ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Objective Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Open Label ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma

TPS11581 Background: Metastatic undifferentiated Pleomorphic Sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, efficacy remains limited in the 2nd line setting and beyond. Pazopanib, the only approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: microsatellite instability-high (MSI-H) cancer and biliary tract cancer. The activity of envafolimab appears to be similar to other PD-1 antibodies administered i.v. Envafolimab demonstrated a 32% objective response rate (ORR) in MSI-H colorectal cancer patients who failed three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patient populations, respectively. The rationale for the ENVASARC trial is based on the previously reported activity of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ̃25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n = 80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (cohort B; n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT 04480502.

Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3532-3539 ◽  
Author(s):  
Lillian Sung ◽  
Beverly J. Lange ◽  
Robert B. Gerbing ◽  
Todd A. Alonzo ◽  
James Feusner
Keyword(s):  
Body Mass Index ◽  
Acute Myeloid Leukemia ◽  
Confidence Interval ◽  
Myeloid Leukemia ◽  
Primary Objective ◽  
Institutional Size ◽  
The Relationship ◽  
Gram Positive Cocci ◽  
Related Mortality ◽  
Acute Myeloid

Abstract The primary objective was to describe the prevalence and characteristics of microbiologically defined infections and infection-related mortality (IRM) in 492 children with acute myeloid leukemia enrolled on CCG 2961. Secondary objectives were to determine the relationship between demographic, disease-related, and therapeutic variables, and infections and IRM. Institutions documented infections prospectively. Age, ethnicity, body mass index, leukemia karyotype, treatment, and institutional size were examined for association with infection outcomes. More than 60% of children experienced such infections in each of 3 phases of chemotherapy. There were 58 infectious deaths; cumulative incidence of IRM was 11% plus or minus 2%. Thirty-one percent of infectious deaths were associated with Aspergillus, 25.9% with Candida, and 15.5% with alpha hemolytic streptococci. Age older than 16 years (hazard ratio [HR], 3.32; 95% confidence interval [CI], 1.87-5.89; P < .001), nonwhite ethnicity (HR, 1.85; 95% CI, 1.10-3.09; P = .02), and underweight status (HR, 3.06; 95% CI, 1.51-6.22; P = .002) were associated with IRM, while size of the treating institution was not. Thus, age, ethnicity, and BMI were important contributors to IRM. Fungi and Gram-positive cocci were the most common organisms associated with IRM and, in particular, Aspergillus species was the largest contributor to infectious deaths.

scholarly journals QUIESCENT COSMOLOGY AND THE FINAL STATE OF THE UNIVERSE

2008 ◽  
Vol 17 (03n04) ◽  
pp. 571-576 ◽  
Author(s):  
PHILIPP A. HÖHN ◽  
SUSAN M. SCOTT
Keyword(s):  
Mathematical Formulation ◽  
Primary Objective ◽  
Mathematical Framework ◽  
Final States ◽  
Structure And Properties ◽  
Initial State ◽  
Final State ◽  
Future Singularity ◽  
Definition Of ◽  
The Universe

It has long been a primary objective of cosmology to understand the apparent isotropy in our universe and to provide a mathematical formulation for its evolution. A promising school of thought for its explanation is quiescent cosmology, which already possesses a mathematical framework, namely the definition of an isotropic singularity, but only for the initial state of the universe. A complementary framework is necessary in order to also describe possible final states of the universe. Our new definitions of an anisotropic future endless universe and an anisotropic future singularity, whose structure and properties differ significantly from those of the isotropic singularity, offer a promising realization for this framework. The combination of the three definitions together may then provides the first complete formalization of the quiescent cosmology concept.

scholarly journals Results of a Double-Blind, Randomized Trial of Ceftobiprole Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria

2007 ◽  
Vol 52 (1) ◽  
pp. 37-44 ◽  
Author(s):  
Gary J. Noel ◽  
Richard S. Strauss ◽  
Karen Amsler ◽  
Markus Heep ◽  
Rienk Pypstra ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Study Drug ◽  
Primary Objective ◽  
Gram Positive ◽  
Taste Disturbance ◽  
Double Blind ◽  
Skin Structure ◽  
Gram Positive Bacteria ◽  
Complicated Skin ◽  
Cure Rates

ABSTRACT Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, −4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, −8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.

scholarly journals Evaluating risk detection methods to uncover ontogenic-mediated adverse drug effect mechanisms in children

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Nicholas P. Giangreco ◽  
Nicholas P. Tatonetti
Keyword(s):  
Adverse Event ◽  
Child Development ◽  
Proportional Reporting Ratio ◽  
Temporal Trends ◽  
Population Modeling ◽  
Detection Methods ◽  
Drug Event ◽  
Event Reporting ◽  
Development Stages ◽  
Stratification Method

Abstract Background Identifying adverse drugs effects (ADEs) in children, overall and within pediatric age groups, is essential for preventing disability and death from marketed drugs. At the same time, however, detection is challenging due to dynamic biological processes during growth and maturation, called ontogeny, that alter pharmacokinetics and pharmacodynamics. As a result, methodologies in pediatric drug safety have been limited to event surveillance and have not focused on investigating adverse event mechanisms. There is an opportunity to identify drug event patterns within observational databases for evaluating ontogenic-mediated adverse event mechanisms. The first step of which is to establish statistical models that can identify temporal trends of adverse effects across childhood. Results Using simulation, we evaluated a population stratification method (the proportional reporting ratio or PRR) and a population modeling method (the generalized additive model or GAM) to identify and quantify ADE risk at varying reporting rates and dynamics. We found that GAMs showed improved performance over the PRR in detecting dynamic drug event reporting across child development stages. Moreover, GAMs exhibited normally distributed and robust ADE risk estimation at all development stages by sharing information across child development stages. Conclusions Our study underscores the opportunity for using population modeling techniques, which leverage drug event reporting across development stages, as biologically-inspired detection methods for evaluating ontogenic mechanisms.

scholarly journals Improved Detection Criteria for Detecting Drug-Drug Interaction Signals Using the Proportional Reporting Ratio

2020 ◽  
Vol 14 (1) ◽  
pp. 4
Author(s):  
Yoshihiro Noguchi ◽  
Keisuke Aoyama ◽  
Satoaki Kubo ◽  
Tomoya Tachi ◽  
Hitomi Teramachi
Keyword(s):  
Drug Interaction ◽  
Confidence Interval ◽  
Drug Interactions ◽  
Signal Detection ◽  
Proportional Reporting Ratio ◽  
Detection Accuracy ◽  
Detection Algorithms ◽  
Proposed Model ◽  
Signal Score ◽  
Drug Drug Interaction

There is a current demand for “safety signal” screening, not only for single drugs but also for drug-drug interactions. The detection of drug-drug interaction signals using the proportional reporting ratio (PRR) has been reported, such as through using the combination risk ratio (CRR). However, the CRR does not consider the overlap between the lower limit of the 95% confidence interval of the PRR of concomitant-use drugs and the upper limit of the 95% confidence interval of the PRR of single drugs. In this study, we proposed the concomitant signal score (CSS), with the improved detection criteria, to overcome the issues associated with the CRR. “Hypothetical” true data were generated through a combination of signals detected using three detection algorithms. The signal detection accuracy of the analytical model under investigation was verified using machine learning indicators. The CSS presented improved signal detection when the number of reports was ≥3, with respect to the following metrics: accuracy (CRR: 0.752 → CSS: 0.817), Youden’s index (CRR: 0.555 → CSS: 0.661), and F-measure (CRR: 0.780 → CSS: 0.820). The proposed model significantly improved the accuracy of signal detection for drug-drug interactions using the PRR.

scholarly journals Analysis of chemotherapy-induced peripheral neuropathy using the Japanese Adverse Drug Event Report database

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Misaki Inoue ◽  
Kiyoka Matsumoto ◽  
Mizuki Tanaka ◽  
Yu Yoshida ◽  
Riko Satake ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Peripheral Neuropathy ◽  
Confidence Interval ◽  
Median Duration ◽  
Adverse Drug Event ◽  
Vinca Alkaloid ◽  
Interquartile Range ◽  
Drug Event ◽  
Event Report ◽  
Time To Onset

AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event associated with several antineoplastic drugs; however, the precise risks and time course of reactions of particular drugs are not clearly understood. The aim of this study was to evaluate the relationship between anticancer agents and CIPN development using data from the Japanese Adverse Drug Event Report (JADER) database and to characterize the time-to-onset and outcomes of CIPN. Chemotherapy-induced peripheral neuropathy was defined using the Medical Dictionary for Regulatory Activities preferred terms. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with 95% confidence interval for signal detection. Data of nine Anatomical Therapeutic Chemical (ATC) drug categories correlated with CIPN development, in addition to the data of the time-to-onset and outcomes. Among 622,289 reports in the JADER database from April 2004 to March 2020, there were 1883 reports of adverse events corresponding to peripheral neuropathy. The ROR (95% confidence interval) for vinblastine, sorbent-based paclitaxel (sb-PTX), oxaliplatin, and bortezomib was 20.4 (12.5–33.4), 13.6 (11.9–15.7), 26.2 (23.6–29.1), and 30.8 (26.6–35.8), respectively. The median duration (interquartile range) to CIPN development after the administration of vinca alkaloids and analogues, taxanes, platinum compounds, and monoclonal antibodies was 11.0 (5.0–46.5), 22.5 (6.0–82.5), 22.0 (6.0–68.5), and 32.5 (11.3–73.8) days, respectively. The median duration (interquartile range) of sb-PTX and nanoparticle albumin-bound (nab)-PTX was 35.0 (7.0–94.0) and 5.5 (3.0–29.3) days, respectively. Our analysis of records in the JADER database revealed several drugs associated with a high risk for CIPN development. In particular, the development of CIPN after vinca alkaloid administration should be closely monitored for 2 weeks after administration. CIPN caused by nab-PTX showed significantly faster onset than that by sb-PTX. Patients who receive taxanes or monoclonal antibodies often do not show an improvement; accordingly, early treatment is required.

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