Browsing by Author "Betensky, Rebecca A"
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Item Open Access An optimal Wilcoxon-Mann-Whitney test of mortality and a continuous outcome.(Stat Methods Med Res, 2016-01-01) Matsouaka, Roland A; Singhal, Aneesh B; Betensky, Rebecca AWe consider a two-group randomized clinical trial, where mortality affects the assessment of a follow-up continuous outcome. Using the worst-rank composite endpoint, we develop a weighted Wilcoxon-Mann-Whitney test statistic to analyze the data. We determine the optimal weights for the Wilcoxon-Mann-Whitney test statistic that maximize its power. We derive a formula for its power and demonstrate its accuracy in simulations. Finally, we apply the method to data from an acute ischemic stroke clinical trial of normobaric oxygen therapy.Item Open Access Calcineurin activation causes retinal ganglion cell degeneration.(Mol Vis, 2012) Qu, Juan; Matsouaka, Roland; Betensky, Rebecca A; Hyman, Bradley T; Grosskreutz, Cynthia LPURPOSE: We previously reported that calcineurin, a Ca(2+)/calmodulin-dependent serine/threonine phosphatase, is activated and proposed that it participates in retinal ganglion cell (RGC) apoptosis in two rodent ocular hypertension models. In this study, we tested whether calcineurin activation by itself, even in the absence of ocular hypertension, is sufficient to cause RGC degeneration. METHODS: We compared RGC and optic nerve morphology after adeno-associated virus serotype 2 (AAV2)-mediated transduction of RGCs with constitutively active calcineurin (CaNCA) or unactivated, wild-type calcineurin (CaNwt). Retinas and optic nerves were harvested 7-16 weeks after injection of the AAV into mouse vitreous. In flatmounted retinas, the transduced RGCs were identified with immunohistochemistry. The morphology of the RGCs was revealed by immunostaining for neurofilament SMI32 or by using GFP-M transgenic mice. A modified Sholl analysis was applied to analyze the RGC dendritic morphology. Optic nerve damage was assessed with optic nerve grading according to the Morrison standard. RESULTS: CaNwt and CaNCA were highly expressed in the injected eyes. Compared to the CaNwt-expressing RGCs, the CaNCA-expressing RGCs had smaller somas, smaller dendritic field areas, shorter total dendrite lengths, and simpler dendritic branching patterns. At 16 weeks, the CaNCA-expressing eyes had greater optic nerve damage than the CaNwt-expressing eyes. CONCLUSIONS: Calcineurin activation is sufficient to cause RGC dendritic degeneration and optic nerve damage. These data support the hypothesis that calcineurin activation is an important mediator of RGC degeneration, and are consistent with the hypothesis that calcineurin activation may contribute to RGC neurodegeneration in glaucoma.Item Open Access Power and sample size calculations for the Wilcoxon-Mann-Whitney test in the presence of death-censored observations.(Stat Med, 2015-02-10) Matsouaka, Roland A; Betensky, Rebecca AWe consider a clinical trial of a potentially lethal disease in which patients are randomly assigned to two treatment groups and are followed for a fixed period of time; a continuous endpoint is measured at the end of follow-up. For some patients; however, death (or severe disease progression) may preclude measurement of the endpoint. A statistical analysis that includes only patients with endpoint measurements may be biased. An alternative analysis includes all randomized patients, with rank scores assigned to the patients who are available for the endpoint measurement on the basis of the magnitude of their responses and with 'worst-rank' scores assigned to those patients whose death precluded the measurement of the continuous endpoint. The worst-rank scores are worse than all observed rank scores. The treatment effect is then evaluated using the Wilcoxon-Mann-Whitney test. In this paper, we derive closed-form formulae for the power and sample size of the Wilcoxon-Mann-Whitney test when missing measurements of the continuous endpoints because of death are replaced by worst-rank scores. We distinguish two approaches for assigning the worst-rank scores. In the tied worst-rank approach, all deaths are weighted equally, and the worst-rank scores are set to a single value that is worse than all measured responses. In the untied worst-rank approach, the worst-rank scores further rank patients according to their time of death, so that an earlier death is considered worse than a later death, which in turn is worse than all measured responses. In addition, we propose four methods for the implementation of the sample size formulae for a trial with expected early death. We conduct Monte Carlo simulation studies to evaluate the accuracy of our power and sample size formulae and to compare the four sample size estimation methods.