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.

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

Characterization of Network-Wide Anomalies in Traffic Flows

Detecting and understanding anomalies in IP networks is an open and ill-defined problem. Toward this end, we have recently proposed the subspace method for anomaly diagnosis. In this paper we present the first large-scale exploration of the power of the subspace method when applied to flow traffic. An important aspect of this approach is that it fuses information from flow measurements taken throughout a network. We apply the subspace method to three different types of sampled flow traffic in a large academic network: multivariate timeseries of byte counts, packet counts, and IP-flow counts. We show that each traffic type brings into focus a different set of anomalies via the subspace method. We illustrate and classify the set of anomalies detected. We find that almost all of the anomalies detected represent events of interest to network operators. Furthermore, the anomalies span a remarkably wide spectrum of event types, including denial of service attacks (single-source and distributed), flash crowds, port scanning, downstream traffic engineering, high-rate flows, worm propagation, and network outage.

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.

Forewarding in Mobile Opportunistic Networks

Recent advances in processor speeds, mobile communications and battery life have enabled computers to evolve from completely wired to completely mobile. In the most extreme case, all nodes are mobile and communication takes place at available opportunities – using both traditional communication infrastructure as well as the mobility of intermediate nodes. These are mobile opportunistic networks. Data communication in such networks is a difficult problem, because of the dynamic underlying topology, the scarcity of network resources and the lack of global information. Establishing end-to-end routes in such networks is usually not feasible. Instead a store-and-carry forwarding paradigm is better suited for such networks. This dissertation describes and analyzes algorithms for forwarding of messages in such networks. In order to design effective forwarding algorithms for mobile opportunistic networks, we start by first building an understanding of the set of all paths between nodes, which represent the available opportunities for any forwarding algorithm. Relying on real measurements, we enumerate paths between nodes and uncover what we refer to as the path explosion effect. The term path explosion refers to the fact that the number of paths between a randomly selected pair of nodes increases exponentially with time. We draw from the theory of epidemics to model and explain the path explosion effect. This is the first contribution of the thesis, and is a key observation that underlies subsequent results. Our second contribution is the study of forwarding algorithms. For this, we rely on trace driven simulations of different algorithms that span a range of design dimensions. We compare the performance (success rate and average delay) of these algorithms. We make the surprising observation that most algorithms we consider have roughly similar performance. We explain this result in light of the path explosion phenomenon. While the performance of most algorithms we studied was roughly the same, these algorithms differed in terms of cost. This prompted us to focus on designing algorithms with the explicit intent of reducing costs. For this, we cast the problem of forwarding as an optimal stopping problem. Our third main contribution is the design of strategies based on optimal stopping principles which we refer to as Delegation schemes. Our analysis shows that using a delegation scheme reduces cost over naive forwarding by a factor of O(√N), where N is the number of nodes in the network. We further validate this result on real traces, where the cost reduction observed is even greater. Our results so far include a key assumption, which is unbounded buffers on nodes. Next, we relax this assumption, so that the problem shifts to one of prioritization of messages for transmission and dropping. Our fourth contribution is the study of message prioritization schemes, combined with forwarding. Our main result is that one achieves higher performance by assigning higher priorities to young messages in the network. We again interpret this result in light of the path explosion effect.

Space, Time and Learning in the Hippocampus: How Fine Spatial and Temporal Scales Are Expanded into Population Codes for Behavioral Control

The hippocampus participates in multiple functions, including spatial navigation, adaptive timing, and declarative (notably, episodic) memory. How does it carry out these particular functions? The present article proposes that hippocampal spatial and temporal processing are carried out by parallel circuits within entorhinal cortex, dentate gyrus, and CA3 that are variations of the same circuit design. In particular, interactions between these brain regions transform fine spatial and temporal scales into population codes that are capable of representing the much larger spatial and temporal scales that are needed to control adaptive behaviors. Previous models of adaptively timed learning propose how a spectrum of cells tuned to brief but different delays are combined and modulated by learning to create a population code for controlling goal-oriented behaviors that span hundreds of milliseconds or even seconds. Here it is proposed how projections from entorhinal grid cells can undergo a similar learning process to create hippocampal place cells that can cover a space of many meters that are needed to control navigational behaviors. The suggested homology between spatial and temporal processing may clarify how spatial and temporal information may be integrated into an episodic memory.