Comparison of the MOdified NARanjo Causality Scale (MONARCSi) for Individual Case Safety Reports vs. a Reference Standard.

INTRODUCTION: In 2018, we published the MONARCSi algorithmic decision support tool showing high inter-rater agreement, moderate sensitivity, and high specificity compared with drug-event pairs (DEPs) previously reviewed using current, industry-established approaches. Following publication, MONARCSi was implemented as a prototype system to facilitate medical review of individual case safety reports (ICSRs). This paper presents subsequent evaluation of MONARCSi-supported causality assessments against an independent, best achievable reference standard. OBJECTIVE: This paper describes the development of an independent reference standard (i.e., reference comparator) using a sample of DEPs evaluated by Roche subject matter experts (SMEs) and subsequent performance analysis for both the reference standard and MONARCSi. METHODS: Roche collected a random sample of 131 DEPs evaluated by an external vendor using the MONARCSi prototype during 2020, and collectively referred to as the VMON (Vendor using the MONARCSi system for medical review) dataset. An internal group of causality SMEs (aka CAUSMET) were recruited and trained to assess the same DEPs independently using the MONARCSi structure with Global Introspection to determine their individual assessments of causality. The CAUSMET final causality was determined using a majority voting rule. RESULTS: Binary comparison of the aggregate results showed substantial agreement (Gwet kappa = 0.81) between the VMON and reference standard CAUSMET assessments. Bayesian latent class modeling showed that both the reference standard and VMON assessments exhibited similar high posterior mean sensitivity and specificity (CAUSMET: 89 and 93%, respectively; VMON: 87 and 94%, respectively). Finally, comparison of the sensitivity and specificity suggested no obvious difference across groups. CONCLUSION: Analysis of causality results from the assessments by independent internal SMEs using MONARCSi shows there is no obvious difference in performance between the aggregate CAUSMET and VMON assessments based on the comparison of specificity and sensitivity. These results further support use of MONARCSi as a decision support tool for evaluating drug-event causality in a consistent and documentable manner.

Lifetime Fitness, Sex-Specific Life History, and the Maintenance of a Polyphenism.

Polyphenisms-alternative morphs produced through plasticity-can reveal the evolutionary and ecological processes that initiate and maintain diversity within populations. We examined lifetime fitness consequences of two morphs in a polyphenic population of Arizona tiger salamanders using a 27-year data set with 1,317 adults and 6,862 captures across eight generations. Larval salamanders develop into either an aquatic paedomorph that retains larval traits and stays in its natal pond or a terrestrial metamorph that undergoes metamorphosis. To evaluate the adaptive significance of this polyphenism, we compared lifetime reproductive success of each morph and assessed how life-history strategies and spatiotemporal variation explained fitness. We found sex-specific differences in lifetime fitness between morphs. For males, paedomorphs had more reproductive opportunities than metamorphs when we accounted for the potential mating advantage of larger males. For females, in contrast, metamorphs had higher estimated egg production than paedomorphs. Life-history strategies differed between morphs largely because the morphs maximized different ends of the trade-off between age at first reproduction and longevity. Spatiotemporal variation affected larval more than adult life-history traits, with little to no effect on lifetime fitness. Thus, environmental variation likely explains differences in morph production across time and space but contributes little to lifetime fitness differences between morphs and sexes. Our long-term study and measures of lifetime fitness provide unique insight into the complex selective regimes potentially acting on each morph and sex. Our findings motivate future work to examine how sex-specific selection may contribute to the maintenance of polyphenism.

An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma.

Using a mouse model of ependymoma-a chemoresistant brain tumor-we combined multicell high-throughput screening (HTS), kinome-wide binding assays, and in vivo efficacy studies, to identify potential treatments with predicted toxicity against neural stem cells (NSC). We identified kinases within the insulin signaling pathway and centrosome cycle as regulators of ependymoma cell proliferation, and their corresponding inhibitors as potential therapies. FDA approved drugs not currently used to treat ependymoma were also identified that posses selective toxicity against ependymoma cells relative to normal NSCs both in vitro and in vivo, e.g., 5-fluorouracil. Our comprehensive approach advances understanding of the biology and treatment of ependymoma including the discovery of several treatment leads for immediate clinical translation.

A randomized controlled trial investigating the effects of celecoxib in patients with localized prostate cancer.

UNLABELLED: Cyclooxygenase-2 (COX-2) is associated with tumour promotion, inhibition of apoptosis, angiogenesis and metastasis. Celecoxib, a selective COX-2 inhibitor was investigated, in patients with clinically localized prostate cancer using immunohistochemistry. PATIENTS AND METHODS: Patients with cT1-2 prostate cancer (n=45) were randomized to celecoxib 400mg b.d. or no treatment for four weeks prior to radical prostatectomy. Histological sections of preoperative biopsy and matched radical prostatectomy specimens were stained for markers of cell proliferation (MIB-1/Ki-67), microvessel density (CD-31 with Weidner scoring), COX-2, apoptosis (TUNEL analysis), angiogenic factors (VEGF and KDR) and HIF-1. RESULTS: Celecoxib decreased tumour cell proliferation, microvessel density, angiogenesis and HIF-1 whilst enhancing apoptosis. These effects approached statistical significance in a multivariate model and the cell proliferation index approached statistical significance on univariate analysis. CONCLUSION: In this pilot study a 4 week regimen of celecoxib resulted in measurable biological effects in prostate cancer tissue. These findings warrant further investigation.