Use of TreeScan by Non-Sentinel Investigators

The TreeScan™ approach has also been utilized by non-Sentinel investigators. Below is a list of presentations or publications of how others have used TreeScan in academia or industry.

Comparison of Data Mining Methods for the Signal Detection of Adverse Drug Events with a Hierarchical Structure in Postmarketing Surveillance

Park G, Jung H, Heo SJ, Jung I
August 5, 2020

There are several different proposed data mining methods for the postmarketing surveillance of drug safety. Adverse events are often classified into a hierarchical structure. Our objective was to compare the performance of several of these different data mining methods for adverse drug events data with a hierarchical structure. We generated datasets based on the World Health Organization's Adverse Reaction Terminology (WHO-ART) hierarchical structure. We evaluated different data mining methods for signal detection, including several frequentist methods such as reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), the likelihood ratio test-based method (LRT), and Bayesian methods such as gamma Poisson shrinker (GPS), Bayesian confidence propagating neural network (BCPNN), the new IC method, and the simplified Bayesian method (sB), as well as the tree-based scan statistic through an extensive simulation study. We also applied the methods to real data on two diabetes drugs, voglibose and acarbose, from the Korea Adverse event reporting system. Only the tree-based scan statistic method maintained the type I error rate at the desired level. Likelihood ratio test-based methods and Bayesian methods tended to be more conservative than other methods in the simulation study and detected fewer signals in the real data example. No method was superior to the others in terms of the statistical power and sensitivity of detecting true signals. It is recommended that those conducting drug‒adverse event surveillance use not just one method, but make a decision based on several methods.

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Safety Surveillance of Pneumococcal Vaccine Using Three Algorithms: Disproportionality Methods, Empirical Bayes Geometric Mean, and Tree-Based Scan Statistic

Lee H, Kim JH, Choe YJ, Shin JY
May 22, 2020

Diverse algorithms for signal detection exist. However, inconsistent results are often encountered among the algorithms due to different levels of specificity used in defining the adverse events (AEs) and signal threshold. We aimed to explore potential safety signals for two pneumococcal vaccines in a spontaneous reporting database and compare the results and performances among the algorithms. Safety surveillance was conducted using the Korea national spontaneous reporting database from 1988 to 2017. Safety signals for pneumococcal vaccine and its subtypes were detected using the following the algorithms: disproportionality methods comprising of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC); empirical Bayes geometric mean (EBGM); and tree-based scan statistics (TSS). Moreover, the performances of these algorithms were measured by comparing detected signals with the known AEs or pneumococcal vaccines (reference standard). Among 10,380 vaccine-related AEs, 1135 reports and 101 AE terms were reported following pneumococcal vaccine. IC generated the most safety signals for pneumococcal vaccine (40/101), followed by PRR and ROR (19/101 each), TSS (15/101), and EBGM (1/101). Similar results were observed for its subtypes. Cellulitis was the only AE detected by all algorithms for pneumococcal vaccine. TSS showed the best balance in the performance: the highest in accuracy, negative predictive value, and area under the curve (70.3%, 67.4%, and 64.2%). Discrepancy in the number of detected signals was observed between algorithms. EBGM and TSS calibrated noise better than disproportionality methods, and TSS showed balanced performance. Nonetheless, these results should be interpreted with caution due to a lack of a gold standard for signal detection.

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Using the Self-Controlled Tree-Temporal Scan Statistic to Assess the Safety of Live Attenuated Herpes Zoster Vaccine

Yih WK, Kulldorff M, Dashevsky I, Maro J
May 7, 2019

The self-controlled tree-temporal scan statistic allows detection of potential vaccine- or drug-associated adverse events without pre-specifying the specific events or post-exposure risk intervals of concern. It thus opens a promising new avenue for safety studies. The method has been successfully used to evaluate the safety of two vaccines for adolescents and young adults, but its suitability to study vaccines for older adults had not been established. The current study applied the method to assess the safety of live attenuated herpes zoster vaccination during 2011-2017 in U.S. adults ≥ 60 years old, using claims data from Truven Health MarketScan® Research Databases. Counts of International Classification of Diseases diagnosis codes recorded in emergency department or hospital settings were scanned for any statistically unusual clustering within a hierarchical tree structure of diagnoses and within 42 days after vaccination. Among 1.24 million vaccinations, four clusters were found: cellulitis on Days 1-3, non-specific erythematous condition on Days 2-4, "other complications…" on Days 1-3, and non-specific allergy on Days 1-6. These results are consistent with local injection-site reactions and other known, generally mild vaccine-associated adverse events and a favorable safety profile. This method may be useful for assessing the safety of other vaccines for older adults. 

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Bacillus Calmette-Guérin (BCG) Vaccine Safety Surveillance in the Korea Adverse Event Reporting System Using the Tree-Based Scan Statistic and Conventional Disproportionality-Based Algorithms

Kim JH, Lee H, Shin JY
May 6, 2020

Substantial variations in the safety profiles of different formulations of the bacillus Calmette-Guérin (BCG) vaccine exist. Therefore, we aimed to detect safety signals of BCG vaccine for intradermal injection (BCG-ID) and percutaneous injection (BCG-PC) in the Korea Adverse Event Reporting System (KAERS). We conducted a vaccine safety surveillance study from the adverse events (AEs) reported following BCG vaccine in the Korea Institute of Drug Safety and Risk Management KAERS Database (KIDS-KD) between 2005 and 2017. We used the tree-based scan statistic (TSS) and four disproportionality-based algorithms for signal detection: empirical Bayesian geometric mean; proportional reporting ratio; reporting odds ratio; and information component. The detected signals from each algorithm was compared with the known AEs of BCG vaccine (reference standard) to present positive predictive value (PPV) and area under the receiver operating curve (AUC).

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An Implementation and Visualization of the Tree-Based Scan Statistic for Safety Event Monitoring in Longitudinal Electronic Health Data

Schachterle SE, Hurley S, Liu Q, Petronis KR, Bate A
January 8, 2019

Longitudinal electronic healthcare data hold great potential for drug safety surveillance. The tree-based scan statistic (TBSS), as implemented by the TreeScan® software, allows for hypothesis-free signal detection in longitudinal data by grouping safety events according to branching, hierarchical data coding systems, and then identifying signals of disproportionate recording (SDRs) among the singular events or event groups. The objective of this analysis was to identify and visualize SDRs with the TBSS in historical data from patients using two antifungal drugs, itraconazole or terbinafine. By examining patients who used either itraconazole or terbinafine, we provide a conceptual replication of a previous TBSS analyses by varying methodological choices and using a data source that had not been previously used with the TBSS, i.e., the Optum Clinformatics™ claims database. With this analysis, we aimed to test a parsimonious design that could be the basis of a broadly applicable method for multiple drug and safety event pairs. 

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Tree-Based Scan Statistic - Application in Manufacturing-Related Safety Signal Detection

Mahaux O, Bauchau V, Zeinoun Z, Van Holle L
January 3, 2019

Over the last decades, medicinal regulations have been put into place and have considerably improved manufacturing practices. Nevertheless, safety issues may still arise. Using the simulation described in this manuscript, our aim is to develop adequate detection methods for manufacturing-related safety signals, especially in the context of biological products. Pharmaceutical companies record the entire batch genealogies, from seed batches over intermediates to final product (FP) batches. We constructed a hierarchical tree based on this genealogy information and linked it to the spontaneous safety data available for the FP batch numbers. The tree-based scan statistic (TBSS) was used on simulated data as a proof of concept to locate the source that may have subsequently generated an excess of specific adverse events (AEs) within the manufacturing steps, and to evaluate the method's adjustment for multiple testing.

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Meningococcal Conjugate Vaccine Safety Surveillance in the Vaccine Safety Datalink Using a Tree-Temporal Scan Data Mining Method

Li R, Weintraub E, McNeil MM, Kulldorff M, Lewis EM, Nelson J, Xu S, Qian L, Klein NP, Destefano F
February 18, 2018

The objective of this study was to conduct a data mining analysis to identify potential adverse events (AEs) following MENACWY-D using the tree-temporal scan statistic in the Vaccine Safety Datalink population and demonstrate the feasibility of this method in a large distributed safety data setting. Traditional pharmacovigilance techniques used in vaccine safety are generally geared to detecting AEs based on pre-defined sets of conditions or diagnoses. Using a newly developed tree-temporal scan statistic data mining method, a pilot study was performed to evaluate the safety profile of the meningococcal conjugate vaccine Menactra® (MenACWY-D), screening thousands of potential AE diagnoses and diagnosis groupings. The study cohort included enrolled participants in the Vaccine Safety Datalink aged 11 to 18 years who had received MenACWY-D vaccination(s) between 2005 and 2014. The tree-temporal scan statistic was employed to identify statistical associations (signals) of AEs following MENACWY-D at a 0.05 level of significance, adjusted for multiple testing. 

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