Quantitative Analysis of Single Nucleotide Polymorphisms within Copy Number Variation

Background Single nucleotide polymorphisms (SNPs) have been used extensively in genetics and epidemiology studies. Traditionally, SNPs that did not pass the Hardy-Weinberg equilibrium (HWE) test were excluded from these analyses. Many investigators have addressed possible causes for departure from HWE, including genotyping errors, population admixture and segmental duplication. Recent large-scale surveys have revealed abundant structural variations in the human genome, including copy number variations (CNVs). This suggests that a significant number of SNPs must be within these regions, which may cause deviation from HWE. Results We performed a Bayesian analysis on the potential effect of copy number variation, segmental duplication and genotyping errors on the behavior of SNPs. Our results suggest that copy number variation is a major factor of HWE violation for SNPs with a small minor allele frequency, when the sample size is large and the genotyping error rate is 0~1%. Conclusions Our study provides the posterior probability that a SNP falls in a CNV or a segmental duplication, given the observed allele frequency of the SNP, sample size and the significance level of HWE testing.

Demand-based Document Dissemination for the World-Wide Web

We analyzed the logs of our departmental HTTP server http://cs-www.bu.edu as well as the logs of the more popular Rolling Stones HTTP server http://www.stones.com. These servers have very different purposes; the former caters primarily to local clients, whereas the latter caters exclusively to remote clients all over the world. In both cases, our analysis showed that remote HTTP accesses were confined to a very small subset of documents. Using a validated analytical model of server popularity and file access profiles, we show that by disseminating the most popular documents on servers (proxies) closer to the clients, network traffic could be reduced considerably, while server loads are balanced. We argue that this process could be generalized so as to provide for an automated demand-based duplication of documents. We believe that such server-based information dissemination protocols will be more effective at reducing both network bandwidth and document retrieval times than client-based caching protocols [2].

Program Representation Size in an Intermediate Language with Intersection and Union Types

The CIL compiler for core Standard ML compiles whole programs using a novel typed intermediate language (TIL) with intersection and union types and flow labels on both terms and types. The CIL term representation duplicates portions of the program where intersection types are introduced and union types are eliminated. This duplication makes it easier to represent type information and to introduce customized data representations. However, duplication incurs compile-time space costs that are potentially much greater than are incurred in TILs employing type-level abstraction or quantification. In this paper, we present empirical data on the compile-time space costs of using CIL as an intermediate language. The data shows that these costs can be made tractable by using sufficiently fine-grained flow analyses together with standard hash-consing techniques. The data also suggests that non-duplicating formulations of intersection (and union) types would not achieve significantly better space complexity.

On the Performance and Robustness of Managing Reliable Transport Connections

We revisit the problem of connection management for reliable transport. At one extreme, a pure soft-state (SS) approach (as in Delta-t [9]) safely removes the state of a connection at the sender and receiver once the state timers expire without the need for explicit removal messages. And new connections are established without an explicit handshaking phase. On the other hand, a hybrid hard-state/soft-state (HS+SS) approach (as in TCP) uses both explicit handshaking as well as timer-based management of the connection’s state. In this paper, we consider the worst-case scenario of reliable single-message communication, and develop a common analytical model that can be instantiated to capture either the SS approach or the HS+SS approach. We compare the two approaches in terms of goodput, message and state overhead. We also use simulations to compare against other approaches, and evaluate them in terms of correctness (with respect to data loss and duplication) and robustness to bad network conditions (high message loss rate and variable channel delays). Our results show that the SS approach is more robust, and has lower message overhead. On the other hand, SS requires more memory to keep connection states, which reduces goodput. Given memories are getting bigger and cheaper, SS presents the best choice over bandwidth-constrained, error-prone networks.

The Role of Edges and Line-Ends in Illusory Contour Formation

Illusory contours can be induced along directions approximately collinear to edges or approximately perpendicular to the ends of lines. Using a rating scale procedure we explored the relation between the two types of inducers by systematically varying the thickness of inducing elements to result; in varying amounts of "edge-like" or "line-like" induction. Inducers for om illusory figures consisted of concentric rings with arcs missing. Observers judged the clarity and brightness of illusory figures as the number of arcs, their thicknesses, and spacings were parametrically varied. Degree of clarity and amount of induced brightness were both found to be inverted-U functions of the number of arcs. These results mandate that any valid model of illusory contour formation must account for interference effects between parallel lines or between those neural units responsible for completion of boundary signals in directions perpendicular to the ends of thin lines. Line width was found to have an effect on both clarity and brightness, a finding inconsistent with those models which employ only completion perpendicular to inducer orientation.

A Neural Network of Adaptively Timed Reinforcement Learning and Hippocampal Dynamics

A neural model is described of how adaptively timed reinforcement learning occurs. The adaptive timing circuit is suggested to exist in the hippocampus, and to involve convergence of dentate granule cells on CA3 pyramidal cells, and NMDA receptors. This circuit forms part of a model neural system for the coordinated control of recognition learning, reinforcement learning, and motor learning, whose properties clarify how an animal can learn to acquire a delayed reward. Behavioral and neural data are summarized in support of each processing stage of the system. The relevant anatomical sites are in thalamus, neocortex, hippocampus, hypothalamus, amygdala, and cerebellum. Cerebellar influences on motor learning are distinguished from hippocampal influences on adaptive timing of reinforcement learning. The model simulates how damage to the hippocampal formation disrupts adaptive timing, eliminates attentional blocking, and causes symptoms of medial temporal amnesia. It suggests how normal acquisition of subcortical emotional conditioning can occur after cortical ablation, even though extinction of emotional conditioning is retarded by cortical ablation. The model simulates how increasing the duration of an unconditioned stimulus increases the amplitude of emotional conditioning, but does not change adaptive timing; and how an increase in the intensity of a conditioned stimulus "speeds up the clock", but an increase in the intensity of an unconditioned stimulus does not. Computer simulations of the model fit parametric conditioning data, including a Weber law property and an inverted U property. Both primary and secondary adaptively timed conditioning are simulated, as are data concerning conditioning using multiple interstimulus intervals (ISIs), gradually or abruptly changing ISis, partial reinforcement, and multiple stimuli that lead to time-averaging of responses. Neurobiologically testable predictions are made to facilitate further tests of the model.

The Role of Edges and Line-Ends in Illusory Contour Formation

Illusory contours can be induced along direction approximately collinear to edges or approximately perpendicular to the ends of lines. Using a rating scale procedure we explored the relation between the two types of inducers by systematically varying the thickness of inducing elements to result in varying amounts of "edge-like" or "line-like" induction. Inducers for our illusory figures consisted of concentric rings with arcs missing. Observers judged the clarity and brightness of illusory figures as the number of arcs, their thicknesses, and spacings were parametrically varied. Degree of clarity and amount of induced brightness were both found to be inverted-U functions of the number of arcs. These results mandate that any valid model of illusory contour formation must account for interference effects between parallel lines or between those neural units responsible for completion of boundary signals in directions perpendicular to the ends of thin lines. Line width was found to have an efFect on both clarity and brightness, a finding inconsistent with those models which employ only completion perpendicular to inducer orientation.