A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

BACKGROUND:Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.METHODS:In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency [greater than or equal to]10%, genotypic call rate [greater than or equal to]80%, and Hardy-Weinberg equilibrium p [greater than or equal to] 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).RESULTS:Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.CONCLUSION:Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., < 1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.

On Learning Counting Functions With Queries

We investigate the problem of learning disjunctions of counting functions, which are general cases of parity and modulo functions, with equivalence and membership queries. We prove that, for any prime number p, the class of disjunctions of integer-weighted counting functions with modulus p over the domain Znq (or Zn) for any given integer q ≥ 2 is polynomial time learnable using at most n + 1 equivalence queries, where the hypotheses issued by the learner are disjunctions of at most n counting functions with weights from Zp. The result is obtained through learning linear systems over an arbitrary field. In general a counting function may have a composite modulus. We prove that, for any given integer q ≥ 2, over the domain Zn2, the class of read-once disjunctions of Boolean-weighted counting functions with modulus q is polynomial time learnable with only one equivalence query, and the class of disjunctions of log log n Boolean-weighted counting functions with modulus q is polynomial time learnable. Finally, we present an algorithm for learning graph-based counting functions.

Speculative Concurrency Control for Real-Time Databases

In this paper, we propose a new class of Concurrency Control Algorithms that is especially suited for real-time database applications. Our approach relies on the use of (potentially) redundant computations to ensure that serializable schedules are found and executed as early as possible, thus, increasing the chances of a timely commitment of transactions with strict timing constraints. Due to its nature, we term our concurrency control algorithms Speculative. The aforementioned description encompasses many algorithms that we call collectively Speculative Concurrency Control (SCC) algorithms. SCC algorithms combine the advantages of both Pessimistic and Optimistic Concurrency Control (PCC and OCC) algorithms, while avoiding their disadvantages. On the one hand, SCC resembles PCC in that conflicts are detected as early as possible, thus making alternative schedules available in a timely fashion in case they are needed. On the other hand, SCC resembles OCC in that it allows conflicting transactions to proceed concurrently, thus avoiding unnecessary delays that may jeopardize their timely commitment.

Geometric Generalizations of the Power of Two Choices

A well-known paradigm for load balancing in distributed systems is the``power of two choices,''whereby an item is stored at the less loaded of two (or more) random alternative servers. We investigate the power of two choices in natural settings for distributed computing where items and servers reside in a geometric space and each item is associated with the server that is its nearest neighbor. This is in fact the backdrop for distributed hash tables such as Chord, where the geometric space is determined by clockwise distance on a one-dimensional ring. Theoretically, we consider the following load balancing problem. Suppose that servers are initially hashed uniformly at random to points in the space. Sequentially, each item then considers d candidate insertion points also chosen uniformly at random from the space,and selects the insertion point whose associated server has the least load. For the one-dimensional ring, and for Euclidean distance on the two-dimensional torus, we demonstrate that when n data items are hashed to n servers,the maximum load at any server is log log n / log d + O(1) with high probability. While our results match the well-known bounds in the standard setting in which each server is selected equiprobably, our applications do not have this feature, since the sizes of the nearest-neighbor regions around servers are non-uniform. Therefore, the novelty in our methods lies in developing appropriate tail bounds on the distribution of nearest-neighbor region sizes and in adapting previous arguments to this more general setting. In addition, we provide simulation results demonstrating the load balance that results as the system size scales into the millions.

Quantum Lower Bounds for Fanout

We prove several new lower bounds for constant depth quantum circuits. The main result is that parity (and hence fanout) requires log depth circuits, when the circuits are composed of single qubit and arbitrary size Toffoli gates, and when they use only constantly many ancillae. Under this constraint, this bound is close to optimal. In the case of a non-constant number of ancillae, we give a tradeoff between the number of ancillae and the required depth.

Application-Level Document Caching in the Internet

With the increasing demand for document transfer services such as the World Wide Web comes a need for better resource management to reduce the latency of documents in these systems. To address this need, we analyze the potential for document caching at the application level in document transfer services. We have collected traces of actual executions of Mosaic, reflecting over half a million user requests for WWW documents. Using those traces, we study the tradeoffs between caching at three levels in the system, and the potential for use of application-level information in the caching system. Our traces show that while a high hit rate in terms of URLs is achievable, a much lower hit rate is possible in terms of bytes, because most profitably-cached documents are small. We consider the performance of caching when applied at the level of individual user sessions, at the level of individual hosts, and at the level of a collection of hosts on a single LAN. We show that the performance gain achievable by caching at the session level (which is straightforward to implement) is nearly all of that achievable at the LAN level (where caching is more difficult to implement). However, when resource requirements are considered, LAN level caching becomes much more desirable, since it can achieve a given level of caching performance using a much smaller amount of cache space. Finally, we consider the use of organizational boundary information as an example of the potential for use of application-level information in caching. Our results suggest that distinguishing between documents produced locally and those produced remotely can provide useful leverage in designing caching policies, because of differences in the potential for sharing these two document types among multiple users.

An Admission Control Paradigm for Real-time Databases

We propose and evaluate an admission control paradigm for RTDBS, in which a transaction is submitted to the system as a pair of processes: a primary task, and a recovery block. The execution requirements of the primary task are not known a priori, whereas those of the recovery block are known a priori. Upon the submission of a transaction, an Admission Control Mechanism is employed to decide whether to admit or reject that transaction. Once admitted, a transaction is guaranteed to finish executing before its deadline. A transaction is considered to have finished executing if exactly one of two things occur: Either its primary task is completed (successful commitment), or its recovery block is completed (safe termination). Committed transactions bring a profit to the system, whereas a terminated transaction brings no profit. The goal of the admission control and scheduling protocols (e.g., concurrency control, I/O scheduling, memory management) employed in the system is to maximize system profit. We describe a number of admission control strategies and contrast (through simulations) their relative performance.

The Network Effects of Prefetching

Prefetching has been shown to be an effective technique for reducing user perceived latency in distributed systems. In this paper we show that even when prefetching adds no extra traffic to the network, it can have serious negative performance effects. Straightforward approaches to prefetching increase the burstiness of individual sources, leading to increased average queue sizes in network switches. However, we also show that applications can avoid the undesirable queueing effects of prefetching. In fact, we show that applications employing prefetching can significantly improve network performance, to a level much better than that obtained without any prefetching at all. This is because prefetching offers increased opportunities for traffic shaping that are not available in the absence of prefetching. Using a simple transport rate control mechanism, a prefetching application can modify its behavior from a distinctly ON/OFF entity to one whose data transfer rate changes less abruptly, while still delivering all data in advance of the user's actual requests.

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.

Securing Bulk Content Almost for Free

Content providers often consider the costs of security to be greater than the losses they might incur without it; many view "casual piracy" as their main concern. Our goal is to provide a low cost defense against such attacks while maintaining rigorous security guarantees. Our defense is integrated with and leverages fast forward error correcting codes, such as Tornado codes, which are widely used to facilitate reliable delivery of rich content. We tune one such family of codes - while preserving their original desirable properties - to guarantee that none of the original content can b e recovered whenever a key subset of encoded packets is missing. Ultimately we encrypt only these key codewords (only 4% of all transmissions), making the security overhead negligible.

A Geometric Approach to Slot Alignment in Wireless Sensor Networks

Traditionally, slotted communication protocols have employed guard times to delineate and align slots. These guard times may expand the slot duration significantly, especially when clocks are allowed to drift for longer time to reduce clock synchronization overhead. Recently, a new class of lightweight protocols for statistical estimation in wireless sensor networks have been proposed. This new class requires very short transmission durations (jam signals), thus the traditional approach of using guard times would impose significant overhead. We propose a new, more efficient algorithm to align slots. Based on geometrical properties of space, we prove that our approach bounds the slot duration by only a constant factor of what is needed. Furthermore, we show by simulation that this bound is loose and an even smaller slot duration is required, making our approach even more efficient.

Wireless and Physical Security via Embedded Sensor Networks

Wireless Intrusion Detection Systems (WIDS) monitor 802.11 wireless frames (Layer-2) in an attempt to detect misuse. What distinguishes a WIDS from a traditional Network IDS is the ability to utilize the broadcast nature of the medium to reconstruct the physical location of the offending party, as opposed to its possibly spoofed (MAC addresses) identity in cyber space. Traditional Wireless Network Security Systems are still heavily anchored in the digital plane of "cyber space" and hence cannot be used reliably or effectively to derive the physical identity of an intruder in order to prevent further malicious wireless broadcasts, for example by escorting an intruder off the premises based on physical evidence. In this paper, we argue that Embedded Sensor Networks could be used effectively to bridge the gap between digital and physical security planes, and thus could be leveraged to provide reciprocal benefit to surveillance and security tasks on both planes. Toward that end, we present our recent experience integrating wireless networking security services into the SNBENCH (Sensor Network workBench). The SNBENCH provides an extensible framework that enables the rapid development and automated deployment of Sensor Network applications on a shared, embedded sensing and actuation infrastructure. The SNBENCH's extensible architecture allows an engineer to quickly integrate new sensing and response capabilities into the SNBENCH framework, while high-level languages and compilers allow novice SN programmers to compose SN service logic, unaware of the lower-level implementation details of tools on which their services rely. In this paper we convey the simplicity of the service composition through concrete examples that illustrate the power and potential of Wireless Security Services that span both the physical and digital plane.

Collocation Games and Their Application to Distributed Resource Management

We introduce Collocation Games as the basis of a general framework for modeling, analyzing, and facilitating the interactions between the various stakeholders in distributed systems in general, and in cloud computing environments in particular. Cloud computing enables fixed-capacity (processing, communication, and storage) resources to be offered by infrastructure providers as commodities for sale at a fixed cost in an open marketplace to independent, rational parties (players) interested in setting up their own applications over the Internet. Virtualization technologies enable the partitioning of such fixed-capacity resources so as to allow each player to dynamically acquire appropriate fractions of the resources for unencumbered use. In such a paradigm, the resource management problem reduces to that of partitioning the entire set of applications (players) into subsets, each of which is assigned to fixed-capacity cloud resources. If the infrastructure and the various applications are under a single administrative domain, this partitioning reduces to an optimization problem whose objective is to minimize the overall deployment cost. In a marketplace, in which the infrastructure provider is interested in maximizing its own profit, and in which each player is interested in minimizing its own cost, it should be evident that a global optimization is precisely the wrong framework. Rather, in this paper we use a game-theoretic framework in which the assignment of players to fixed-capacity resources is the outcome of a strategic "Collocation Game". Although we show that determining the existence of an equilibrium for collocation games in general is NP-hard, we present a number of simplified, practically-motivated variants of the collocation game for which we establish convergence to a Nash Equilibrium, and for which we derive convergence and price of anarchy bounds. In addition to these analytical results, we present an experimental evaluation of implementations of some of these variants for cloud infrastructures consisting of a collection of multidimensional resources of homogeneous or heterogeneous capacities. Experimental results using trace-driven simulations and synthetically generated datasets corroborate our analytical results and also illustrate how collocation games offer a feasible distributed resource management alternative for autonomic/self-organizing systems, in which the adoption of a global optimization approach (centralized or distributed) would be neither practical nor justifiable.

Reliable Cellular Automata with Self-Organization

In a probabilistic cellular automaton in which all local transitions have positive probability, the problem of keeping a bit of information for more than a constant number of steps is nontrivial, even in an infinite automaton. Still, there is a solution in 2 dimensions, and this solution can be used to construct a simple 3-dimensional discrete-time universal fault-tolerant cellular automaton. This technique does not help much to solve the following problems: remembering a bit of information in 1 dimension; computing in dimensions lower than 3; computing in any dimension with non-synchronized transitions. Our more complex technique organizes the cells in blocks that perform a reliable simulation of a second (generalized) cellular automaton. The cells of the latter automaton are also organized in blocks, simulating even more reliably a third automaton, etc. Since all this (a possibly infinite hierarchy) is organized in "software", it must be under repair all the time from damage caused by errors. A large part of the problem is essentially self-stabilization recovering from a mess of arbitrary-size and content caused by the faults. The present paper constructs an asynchronous one-dimensional fault-tolerant cellular automaton, with the further feature of "self-organization". The latter means that unless a large amount of input information must be given, the initial configuration can be chosen to be periodical with a small period.

Trajectory Guided Tracking and Recognition of Actions

A combined 2D, 3D approach is presented that allows for robust tracking of moving people and recognition of actions. It is assumed that the system observes multiple moving objects via a single, uncalibrated video camera. Low-level features are often insufficient for detection, segmentation, and tracking of non-rigid moving objects. Therefore, an improved mechanism is proposed that integrates low-level (image processing), mid-level (recursive 3D trajectory estimation), and high-level (action recognition) processes. A novel extended Kalman filter formulation is used in estimating the relative 3D motion trajectories up to a scale factor. The recursive estimation process provides a prediction and error measure that is exploited in higher-level stages of action recognition. Conversely, higher-level mechanisms provide feedback that allows the system to reliably segment and maintain the tracking of moving objects before, during, and after occlusion. The 3D trajectory, occlusion, and segmentation information are utilized in extracting stabilized views of the moving object that are then used as input to action recognition modules. Trajectory-guided recognition (TGR) is proposed as a new and efficient method for adaptive classification of action. The TGR approach is demonstrated using "motion history images" that are then recognized via a mixture-of-Gaussians classifier. The system was tested in recognizing various dynamic human outdoor activities: running, walking, roller blading, and cycling. Experiments with real and synthetic data sets are used to evaluate stability of the trajectory estimator with respect to noise.