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.

Adaptive Reliable Multicast

An increasing number of applications, such as distributed interactive simulation, live auctions, distributed games and collaborative systems, require the network to provide a reliable multicast service. This service enables one sender to reliably transmit data to multiple receivers. Reliability is traditionally achieved by having receivers send negative acknowledgments (NACKs) to request from the sender the retransmission of lost (or missing) data packets. However, this Automatic Repeat reQuest (ARQ) approach results in the well-known NACK implosion problem at the sender. Many reliable multicast protocols have been recently proposed to reduce NACK implosion. But, the message overhead due to NACK requests remains significant. Another approach, based on Forward Error Correction (FEC), requires the sender to encode additional redundant information so that a receiver can independently recover from losses. However, due to the lack of feedback from receivers, it is impossible for the sender to determine how much redundancy is needed. In this paper, we propose a new reliable multicast protocol, called ARM for Adaptive Reliable Multicast. Our protocol integrates ARQ and FEC techniques. The objectives of ARM are (1) reduce the message overhead due to NACK requests, (2) reduce the amount of data transmission, and (3) reduce the time it takes for all receivers to receive the data intact (without loss). During data transmission, the sender periodically informs the receivers of the number of packets that are yet to be transmitted. Based on this information, each receiver predicts whether this amount is enough to recover its losses. Only if it is not enough, that the receiver requests the sender to encode additional redundant packets. Using ns simulations, we show the superiority of our hybrid ARQ-FEC protocol over the well-known Scalable Reliable Multicast (SRM) protocol.

SomeCast: A Paradigm for Real-Time Adaptive Reliable Multicast

SomeCast is a novel paradigm for the reliable multicast of real-time data to a large set of receivers over the Internet. SomeCast is receiver-initiated and thus scalable in the number of receivers, the diverse characteristics of paths between senders and receivers (e.g. maximum bandwidth and round-trip-time), and the dynamic conditions of such paths (e.g. congestion-induced delays and losses). SomeCast enables receivers to dynamically adjust the rate at which they receive multicast information to enable the satisfaction of real-time QoS constraints (e.g. rate, deadlines, or jitter). This is done by enabling a receiver to join SOME number of concurrent multiCAST sessions, whereby each session delivers a portion of an encoding of the real-time data. By adjusting the number of such sessions dynamically, client-specific QoS constraints can be met independently. The SomeCast paradigm can be thought of as a generalization of the AnyCast (e.g. Dynamic Server Selection) and ManyCast (e.g. Digital Fountain) paradigms, which have been proposed in the literature to address issues of scalability of UniCast and MultiCast environments, respectively. In this paper we overview the SomeCast paradigm, describe an instance of a SomeCast protocol, and present simulation results that quantify the significant advantages gained from adopting such a protocol for the reliable multicast of data to a diverse set of receivers subject to real-time QoS constraints.