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Primary open-angle glaucoma (POAG) is among the leading causes of blindness in the United States and worldwide. While numerous prospective clinical trials have convincingly shown that elevated intraocular pressure (IOP) is a leading risk factor for the development of POAG, an increasingly debated issue in recent years is the effect of IOP fluctuation on the risk of developing POAG. In many applications, this question is addressed via a "naïve" two-step approach where some sample-based estimates (e.g., standard deviation) are first obtained as surrogates for the "true" within-subject variability and then included in Cox regression models as covariates. However, estimates from two-step approach are more likely to suffer from the measurement error inherent in sample-based summary statistics. In this paper we propose a joint model to assess the question whether individuals with different levels of IOP variability have different susceptibility to POAG. In our joint model, the trajectory of IOP is described by a linear mixed model that incorporates patient-specific variance, the time to POAG is fit using a semi-parametric or parametric distribution, and the two models are linked via patient-specific random effects. Parameters in the joint model are estimated under Bayesian framework using Markov chain Monte Carlo (MCMC) methods with Gibbs sampling. The method is applied to data from the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS), two large-scale multi-center randomized trials on the prevention of POAG.

Objective: This report compares the accuracy of 3 prediction models for the development of primary open-angle glaucoma (POAG). The models differ primarily in their handling of these eye-specific variables: intraocular pressure (IOP), central corneal thickness (CCT), vertical cup-to-disc ratio (VCD), and visual field pattern standard deviation (PSD). The "means" model includes age and the means of right and left eyes; the "means plus asymmetry" model includes age, the means of right and left eyes as well as the absolute difference between eyes for eye-specific variables; and the "worse" eye model includes age and values from the eye at higher risk for developing POAG. Design: This report uses data from the observation group of the Ocular Hypertension Treatment Study (OHTS) and the placebo group of the European Glaucoma Prevention Study (EGPS) who have complete data on both eyes at baseline. Performance of the prediction models is assessed using the c-statistic, calibration chi-square, and Pearson correlation coefficient. Participants: The OHTS observation group (n =717; 6.7 years median follow-up) and the EGPS placebo group (n= 324; 4.9 years median follow-up). Testing: Baseline data included demographic characteristics, medical history, ocular examination, visual fields, and optic disc photographs. Main Outcome Measures: Development of reproducible visual field abnormality or optic disc deterioration as determined by masked readers and attributed to POAG by a masked end point committee. Results: Baseline factors that were statistically significant in all predictive models were age, IOP, CCT, VCD, and PSD. Also, statistically significant were baseline asymmetry in IOP and asymmetry in VCD. The c-statistics for the "means" model, "means plus asymmetry" model, and "worse" eye model were 0.74, 0.77, and 0.75, respectively. The calibration chi-square values were 7.32, 11.19, and 1.81, respectively. Correlation coefficients between risk estimates calculated by different m

This report documents the physics case for building a 2 MW, 8 GeV superconducting linac proton driver at Fermilab.

This report documents the physics case for building a 2 MW, 8 GeV superconducting linac proton driver at Fermilab.

Little is known about the signals that promote early B lineage differentiation from common lymphoid progenitors (CLPs). Using a stromal-free culture system, we show that interleukin (IL)-7 is sufficient to promote the in vitro differentiation of CLPs into B220(+) CD19(+) B lineage progenitors. Consistent with current models of early B cell development, surface expression of B220 was initiated before CD19 and was accompanied by the loss of T lineage potential. To address whether IL-7 receptor (R) activity is essential for early B lineage development in vivo, we examined the frequencies of CLPs and downstream pre-pro- and pro-B cells in adult mice lacking either the alpha chain or the common gamma chain (gamma(c)) of the IL-7R. The data indicate that although gamma(c)(-/-) mice have normal frequencies of CLPs, both gamma(c)(-/-) and IL-7R(alpha)(-/-) mice lack detectable numbers of all downstream early B lineage precursors, including pre-pro-B cells. These findings challenge previous notions regarding the point in B cell development affected by the loss of IL-7R signaling and suggest that IL-7 plays a key and requisite role during the earliest phases of B cell development.