Evaluating Treatment Effect in Multicenter Trials with Small Centers Using Survival Modeling

Clinical trials of rare diseases commonly enlist several centers to achieve recruitment goals. The aim of this study is to examine the estimation of treatment effects for survival outcomes in multicenter clinical trials with varying numbers of centers and few patients per center for rarer disease outcomes (i.e. rare cancers). We modeled the heterogeneity between centers using Cox frailty models to account for the variability in patients and patient care between centers and examined measures of model fit via smoothed functions of a prognostic factor. Through a simulation study, we were able to examine the consequence of having only a few centers or a few patients per center on the treatment and prognostic factor effects and model performance indices. Overall, we found it is preferable to have more patients per site and more sites in a multicenter trial as expected. However, having a few patients per site is feasible if there are many sites in a trial

Model Selection in Variational Mixed Effects Models

Variational inference is an alternative estimation technique for Bayesian models. Recent work shows that variational methods provide consistent estimation via efficient, deterministic algorithms. Other tools, such as model selection using variational AICs (VAIC) have been developed and studied for the linear regression case. While mixed effects models have enjoyed some study in the variational context, tools for model selection are lacking. One important feature of model selection in mixed effects models, particularly longitudinal models, is the selection of the random effects which in turn determine the covariance structure for the repeatedly sampled outcome. To address this, we derive a VAIC specifically for variational mixed effects (VME) models. We also implement a parameter-efficient VME as part of our study which reduces any general random effects structure down to a single subject-specific score. This model accommodates a wide range of random effect structures including random intercept and slope models as well as random functional effects. Our VAIC can model and perform selection on a variety of VME models including more classic longitudinal models as well as longitudinal scalar-on-function regression. As we demonstrate empirically, our VAIC performs well in discriminating between correctly and incorrectly specified random effects structures. Finally, we illustrate the use of VAICs for VMEs on two datasets: a study of lead levels in children and a study of diffusion tensor imaging

Overcoming the Obstacles of Garrett: An as Applied Saving Construction for the ADA\u27s Title II

Recent Supreme Court cases regarding Congress\u27s abrogation authority have seriously impaired Congress\u27s ability to demonstrate a valid exercise of its Section 5 power under the Fourteenth Amendment to subject nonconsenting states to suit for money damages in federal court. During its 2003 term, the Supreme Court has again granted certiorari to a case involving the proper scope of Congress\u27s section 5 power, Lane v. Tennessee. Lane involves a suit for money damages under Title II of the ADA based on the alleged failure of the State of Tennessee to make its courthouses accessible. Many commentators suggest that the Supreme Court will follow its current precedent and deny a damage remedy in Lane, particularly since the Court barred a suit for damages brought by a state employee for an alleged violation of Title I of the ADA in Board of Trustees of the University of Alabama v. Garrett. This article critiques the Court\u27s current analysis as seen in Garrett and proposes that the Court should evaluate the ADA\u27s Title II damage remedy against the states differently than it did Title I\u27s. It suggests that the Court should adopt an as applied analysis when deciding Title II damage remedy claims. By examining the specific state program or service alleged to discriminate against the disabled, the Court may apply a different level of scrutiny to the state\u27s action than the rational basis scrutiny that applied in Garrett. For example, in Lane, the fundamental right of access to the state court system has been denied to disabled plaintiffs in Tennessee because the courthouses are inaccessible to those who cannot walk up the stairs. Because the Lane case involves a fundamental right, the Court should apply strict scrutiny when evaluating Title II\u27s congruence and proportionality. Analyzing the Lane case, and other Title II damages claims on the facts and with respect to the right that has allegedly been abridged is the appropriate federalism standard

Overcoming the Obstacles of Garrett: An as Applied Saving Construction for the ADA\u27s Title II

Recent Supreme Court cases regarding Congress\u27s abrogation authority have seriously impaired Congress\u27s ability to demonstrate a valid exercise of its Section 5 power under the Fourteenth Amendment to subject nonconsenting states to suit for money damages in federal court. During its 2003 term, the Supreme Court has again granted certiorari to a case involving the proper scope of Congress\u27s section 5 power, Lane v. Tennessee. Lane involves a suit for money damages under Title II of the ADA based on the alleged failure of the State of Tennessee to make its courthouses accessible. Many commentators suggest that the Supreme Court will follow its current precedent and deny a damage remedy in Lane, particularly since the Court barred a suit for damages brought by a state employee for an alleged violation of Title I of the ADA in Board of Trustees of the University of Alabama v. Garrett. This article critiques the Court\u27s current analysis as seen in Garrett and proposes that the Court should evaluate the ADA\u27s Title II damage remedy against the states differently than it did Title I\u27s. It suggests that the Court should adopt an as applied analysis when deciding Title II damage remedy claims. By examining the specific state program or service alleged to discriminate against the disabled, the Court may apply a different level of scrutiny to the state\u27s action than the rational basis scrutiny that applied in Garrett. For example, in Lane, the fundamental right of access to the state court system has been denied to disabled plaintiffs in Tennessee because the courthouses are inaccessible to those who cannot walk up the stairs. Because the Lane case involves a fundamental right, the Court should apply strict scrutiny when evaluating Title II\u27s congruence and proportionality. Analyzing the Lane case, and other Title II damages claims on the facts and with respect to the right that has allegedly been abridged is the appropriate federalism standard

Estimating and Interpreting Effects from Nonlinear Exposure-Response Curves in Occupational Cohorts Using Truncated Power Basis Expansions and Penalized Splines

Truncated power basis expansions and penalized spline methods are demonstrated for estimating nonlinear exposure-response relationships in the Cox proportional hazards model. R code is provided for fitting models to get point and interval estimates. The method is illustrated using a simulated data set under a known exposure-response relationship and in a data application examining risk of carpal tunnel syndrome in an occupational cohort

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Exposure-response relationships for the ACGIH threshold limit value for hand-activity level: results from a pooled data study of carpal tunnel syndrome

OBJECTIVE: This paper aimed to quantify exposure–response relationships between the American Conference of Governmental Industrial Hygienists’ (ACGIH) threshold limit value (TLV) for hand-activity level (HAL) and incidence of carpal tunnel syndrome (CTS). METHODS: Manufacturing and service workers previously studied by six research institutions had their data combined and re-analyzed. CTS cases were defined by symptoms and abnormal nerve conduction. Hazard ratios (HR) were calculated using proportional hazards regression after adjusting for age, gender, body mass index, and CTS predisposing conditions. RESULTS: The longitudinal study comprised 2751 incident-eligible workers, followed prospectively for up to 6.4 years and contributing 6243 person-years of data. Associations were found between CTS and TLV for HAL both as a continuous variable [HR 1.32 per unit, 95% confidence interval (95% CI) 1.11–1.57] and when categorized using the ACGIH action limit (AL) and TLV. Those between the AL and TLV and above the TLV had HR of 1.7 (95% CI 1.2–2.5) and 1.5 (95% CI 1.0–2.1), respectively. As independent variables (in the same adjusted model) the HR for peak force (PF) and HAL were 1.14 per unit (95% CI 1.05–1.25), and 1.04 per unit (95% CI 0.93–1.15), respectively. CONCLUSION: Those with exposures above the AL were at increased risk of CTS, but there was no further increase in risk for workers above the TLV. This suggests that the current AL may not be sufficiently protective of workers. Combinations of PF and HAL are useful for predicting risk of CTS