ABSTRACT
Purpose: Development and evaluation of a drug-safety signal detection system integrating data-mining tools in longitudinal data is essential. This study aimed to construct a new triage system using longitudinal data for drug-safety signal detection, integrating data-mining tools, and evaluate adaptability of such system. Patients and Methods: Based on relevant guidelines and structural frameworks in Taiwan's pharmacovigilance system, we constructed a triage system integrating sequence symmetry analysis (SSA) and tree-based scan statistics (TreeScan) as data-mining tools for detecting safety signals. We conducted an exploratory analysis utilizing Taiwan's National Health Insurance Database and selecting two drug classes (sodium-glucose co-transporter-2 inhibitors (SGLT2i) and non-fluorinated quinolones (NFQ)) as chronic and episodic treatment respectively, as examples to test feasibility of the system. Results: Under the proposed system, either cohort-based or self-controlled mining with SSA and TreeScan was selected, based on whether the screened drug had an appropriate comparator. All detected alerts were further classified as known adverse drug reactions (ADRs), events related to other causes or potential signals from the triage algorithm, building on existing drug labels and clinical judgement. Exploratory analysis revealed greater numbers of signals for NFQ with a relatively low proportion of known ADRs; most were related to indication, patient characteristics or bias. No safety signals were found. By contrast, most SGLT2i signals were known ADRs or events related to patient characteristics. Four were potential signals warranting further investigation. Conclusion: The proposed system facilitated active and systematic screening to detect and classify potential safety signals. Countries with real-world longitudinal data could adopt it to streamline drug-safety surveillance.
ABSTRACT
Purpose: Analysis of ferning formation after tear drop desiccation on a glass slide has been applied as a simple method to examine tear normality and is referred to as the tear ferning (TF) test. Despite use of the TF test in clinical settings and in some animals, thus far no TF test protocol has been developed for the mouse model. This study aimed to establish a mouse TF test protocol that can be used for dry eye research using the mouse as the study model. Methods: Tear samples were collected from 24 healthy mice after repeated flushes with 2, 5, 10, or 20 µL wash solutions, either 0.9% NaCl saline or sterile water, on the ocular surface. After sample collection, TF tests were performed at variable drop volumes (2-20 µL), at a relative humidity of either 46% ± 2% or 53% ± 2%, and with temperature fixed at 24°C ± 2°C for comparison. Moreover, the influence of osmolarity (between 280 and 360 mOsm/L) and pH values (6.5-8.0) and the effect of centrifugation (4000 rpm, 10 minutes) on ferning formation were examined. Reproducibility and ferning storage stability were also determined. Results: An optimized protocol was established with relative humidity at 46% ± 2% and drop aliquot at 2 µL, using 0.9% NaCl saline as the wash solution. Using sterilized water as the wash solution did not result in any crystalloid formation. Centrifugation did not aid ferning formation in any of the samples. Higher osmolarity increased ferning formation from grades between 0 to 1 to grades between 2 to 3, but pH values that varied between 6.5 and 8.0 did not affect ferning formation. The established mouse TF test protocol also displayed reproducibility and storage stability. Conclusions: A TF test protocol for the mouse model was established that could be used for comparative analyses under various ocular surface disease conditions. Translational Relevance: This mouse TF test protocol will facilitate the application of basic research into the mouse model to clinical care.
