Replication in Genome-Wide Association Studies

Replication helps ensure that a genotype-phenotype association observed in a genome-wide association (GWA) study represents a credible association and is not a chance finding or an artifact due to uncontrolled biases. We discuss prerequisites for exact replication, issues of heterogeneity, advantages and disadvantages of different methods of data synthesis across multiple studies, frequentist vs. Bayesian inferences for replication, and challenges that arise from multi-team collaborations. While consistent replication can greatly improve the credibility of a genotype-phenotype association, it may not eliminate spurious associations due to biases shared by many studies. Conversely, lack of replication in well-powered follow-up studies usually invalidates the initially proposed association, although occasionally it may point to differences in linkage disequilibrium or effect modifiers across studies.Comment: Published in at http://dx.doi.org/10.1214/09-STS290 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?

Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials (both pre-approval and post-approval). However, two recent meta-analyses question this picture. The first meta-analysis used data that were submitted to FDA for the approval of 12 antidepressant drugs. While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results. The average benefit of these drugs based on the FDA data was of small magnitude, while the published literature suggested larger benefits. A second meta-analysis using also FDA-submitted data examined the relationship between treatment effect and baseline severity of depression. Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinically important only in the very small minority of patient populations with severe major depression. In severe major depression, antidepressants did not become more effective, simply placebo lost effectiveness. These data suggest that antidepressants may be less effective than their wide marketing suggests. Short-term benefits are small and long-term balance of benefits and harms is understudied. I discuss how the use of many small randomized trials with clinically non-relevant outcomes, improper interpretation of statistical significance, manipulated study design, biased selection of study populations, short follow-up, and selective and distorted reporting of results has built and nourished a seemingly evidence-based myth on antidepressant effectiveness and how higher evidence standards, with very large long-term trials and careful prospective meta-analyses of individual-level data may reach closer to the truth and clinically useful evidence

The Coherent File Distribution Protocol

CFDP is a protocol that takes advantage of the broadcast nature of CSMA networks to speed up simultaneous one-to-many file transfers (e.g., when booting diskless workstations). The CFDP server listens and services requests for entire files or portions thereof. CFDP clients first determine whether the file they are interested in is already being transferred, in which case they "eavesdrop" and load as much of it as they can, or they initiate a new transfer. The clients timeout when the server stops transmitting, and if they are still missing parts of the file they request them with a block-transfer request. CFDP is a back-end protocol a front end is needed to handle naming and security issues. A simple such front end is also presented here

Notes on the Implementation of a Remote Fork Mechanism

We describe a method for implementing a remote fork, a primitive with the semantics of a UNIX fork() call which begins the execution of the child process on a remote machine. We begin by examining the subject of process migration, and conclude that most of the relevant process state can be captured and transferred to a remote system without operating system support. We then show how our implementation is easily optimized to achieve a performance improvement of greater than 10 times when measuring execution time. We conclude with some comments on limitations and applications of the remote fork mechanism

Implementing Pushback: Router-Based Defense Against DDoS Attacks

Pushback is a mechanism for defending against distributed denial-of-service (DDoS) attacks. DDoS attacks are treated as a congestion-control problem, but because most such congestion is caused by malicious hosts not obeying traditional end-to-end congestion control, the problem must be handled by the routers. Functionality is added to each router to detect and preferentially drop packets that probably belong to an attack. Upstream routers are also notified to drop such packets (hence the term Pushback) in order that the router's resources be used to route legitimate traffic. In this paper we present an architecture for Pushback, its implementation under FreeBSD, and suggestions for how such a system can be implemented in core routers