A Risk‐Adjusted O–E CUSUM with Monitoring Bands for Monitoring Medical Outcomes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97491/1/biom1822.pd

Evaluating Failure Outcomes with Applications to Transplant Facility Performance.

We develop several methods to evaluate mortality experience of medical facilities with applications to transplant facilities' post-transplant mortality and pre-transplant waitlist mortality. We aim to compare the center-specific outcomes with the standard practice while providing timely feedback to the centers. In Chapter II, we introduce a risk-adjusted O-E (Observed-Expected) Cumulative Sum (CUSUM) chart along with monitoring bands as decision criterion, to monitor the post-transplant mortality in transplant programs. This can be used in place of a traditional but complicated V-mask and yields a more simply interpreted chart. The resulting plot provides bounds that allow for simultaneous monitoring of failure time outcomes with signals for `worse than expected' or `better than expected'. The plots are easily interpreted in that their slopes provide graphical estimates of relative risks and direct information on additional failures needed to trigger a signal. In Chapter II, we discuss the construction of a weighted CUSUM to evaluate pre-transplant waitlist mortality of facilities where transplantation can be considered as dependent censoring. Patients are evaluated based on their current medical condition as reflected in a time dependent variable the Model for End-Stage Liver Disease score, which is used to prioritize to receive liver transplants. We assume a ‘standard’ transplant practice through a transplant model, utilizing Inverse Probability Censoring Weights (IPCW) to construct a weighted CUSUM. We evaluate the properties of a weighted zero-mean process as the basis of the proposed weighted CUSUM. A rule of setting control limits is discussed. Case study on regional transplant waitlist mortality is carried out to demonstrate the usage of the proposed weighted CUSUM. In Chapter III, we provide an explicit road map for using a Cox dependent censoring model in the IPCW approach, complete with details of implementation. In addition, we evaluate an alternative parametric IPCW approach to gain efficiency. Simulation studies and case study on the national liver transplant waitlist mortality are conducted to demonstrate the similarity in estimates between Cox IPCW and PWE IPCW, and the computational savings by the PWE IPCW as compared to the Cox IPCW. In the last chapter, we discuss the future directions of our work.PHDBiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96101/1/renajsun_1.pd

A weighted cumulative sum (WCUSUM) to monitor medical outcomes with dependent censoring

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108011/1/sim6139.pd

Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion

Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3$^{+}$ induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CT$^{hi}$, CT$^{lo}$) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CT$^{hi}$ conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CT$^{lo}$- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3$^{+}$ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CT$^{lo}$- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3$^{+}$ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field