Automated method for detecting increases in frequency of spontaneous adverse event reports over time.

A statistical methodology--focused on temporal change detection--was developed to highlight excursions from baseline spontaneous adverse event (AE) reporting. We used regression (both smooth trend and seasonal components) to model the time course of a drug's reports containing an AE, and then compared the sum of counts in the past 2 months with the fitted trend. The signaling threshold was tuned, using retrospective analysis, to yield acceptable sensitivity and specificity. The method may enhance pharmacovigilance by providing effective automated alerting of reporting aberrations when databases are small, when drugs have established safety profiles, and/or when product quality issues are of concern.

Truncated robust distance for clinical laboratory safety data monitoring and assessment.

Laboratory safety data are routinely collected in clinical studies for safety monitoring and assessment. We have developed a truncated robust multivariate outlier detection method for identifying subjects with clinically relevant abnormal laboratory measurements. The proposed method can be applied to historical clinical data to establish a multivariate decision boundary that can then be used for future clinical trial laboratory safety data monitoring and assessment. Simulations demonstrate that the proposed method has the ability to detect relevant outliers while automatically excluding irrelevant outliers. Two examples from actual clinical studies are used to illustrate the use of this method for identifying clinically relevant outliers.

Val64Ile polymorphism in the C-C chemokine receptor 2 is associated with reduced coronary artery calcification.

OBJECTIVE: Studies in mice have shown that genetic disruption of monocyte chemotactic protein-1 or its receptor, the C-C chemokine receptor 2 (CCR2), inhibits atherosclerosis, but few data exist in humans to suggest that the monocyte chemotactic protein-1-CCR2 interaction is important in atherogenesis. A common polymorphism in the human CCR2 gene resulting in a substitution of isoleucine for valine (Val64Ile) has been associated with other disease phenotypes in humans. METHODS AND RESULTS: A cohort of first-degree relatives of persons with premature coronary artery disease was recruited and quantitatively phenotyped for the extent of CAC, a marker of coronary atherosclerosis, by using electron beam CT. The extent of CAC was significantly lower in subjects with the CCR2-Ile64 variant (Val/Ile and Ile/Ile genotypes) than in subjects carrying 2 Val64 alleles, even after adjustment for traditional risk factors. CONCLUSIONS: This study provides genetic evidence linking CCR2 with coronary atherosclerosis in humans.