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

Introduction 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. Objective 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. Methods The TBSS analysis was used to examine incident events and any itraconazole or terbinafine use among US-based patients from 2002 through 2007. Event frequencies before and after the first day of drug exposure were compared over 14- and 56-day periods of observation in a Bernoulli model with a self-controlled design. Safety events were classified into a hierarchical tree structure using the Clinical Classifications Software (CCS) which mapped International Classification of Diseases, 9th Revision (ICD-9) codes to 879 diagnostic groups. Using the TBSS, the log likelihood ratio of observed versus expected events in all groups along the CCS hierarchy were compared, and groups of events that occurred at disproportionally high frequencies were identified as potential SDRs; p-values for the potential SDRs were estimated with Monte-Carlo permutation based methods. Output from TreeScan® was visualized and plotted as a network which followed the CCS tree structure. Results Terbinafine use (n = 223,968) was associated with SDRs for diseases of the circulatory system (14- and 56-day p = 0.001) and heart (14-day p = 0.026 and 56-day p = 0.001) as well as coronary atherosclerosis and other heart disease (14-day p = 0.003 and 56-day p = 0.004). For itraconazole use (n = 36,025), the TBSS identified SDRs for coronary atherosclerosis and other heart disease (p = 0.002) and complications of an implanted or grafted device (14-day p = 0.001 and 56-day p