The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports

BACKGROUND:The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies.METHODS:Adult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests.RESULTS:The participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 +/- 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency [greater than or equal to] 10%, genotype call rate [greater than or equal to] 80%, Hardy-Weinberg equilibrium p-value [greater than or equal to] 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:We have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.

On the Efficiency and Fairness of Transmission Control Loops: A Case for Exogenous Losses

We postulate that exogenous losses-which are typically regarded as introducing undesirable "noise" that needs to be filtered out or hidden from end points-can be surprisingly beneficial. In this paper we evaluate the effects of exogenous losses on transmission control loops, focusing primarily on efficiency and convergence to fairness properties. By analytically capturing the effects of exogenous losses, we are able to characterize the transient behavior of TCP. Our numerical results suggest that "noise" resulting from exogenous losses should not be filtered out blindly, and that a careful examination of the parameter space leads to better strategies regarding the treatment of exogenous losses inside the network. Specifically, we show that while low levels of exogenous losses do help connections converge to their fair share, higher levels of losses lead to inefficient network utilization. We draw the line between these two cases by determining whether or not it is advantageous to hide, or more interestingly introduce, exogenous losses. Our proposed approach is based on classifying the effects of exogenous losses into long-term and short-term effects. Such classification informs the extent to which we control exogenous losses, so as to operate in an efficient and fair region. We validate our results through simulations.

Rule Extraction, Fuzzy ARTMAP, and Medical Databases

This paper shows how knowledge, in the form of fuzzy rules, can be derived from a self-organizing supervised learning neural network called fuzzy ARTMAP. Rule extraction proceeds in two stages: pruning removes those recognition nodes whose confidence index falls below a selected threshold; and quantization of continuous learned weights allows the final system state to be translated into a usable set of rules. Simulations on a medical prediction problem, the Pima Indian Diabetes (PID) database, illustrate the method. In the simulations, pruned networks about 1/3 the size of the original actually show improved performance. Quantization yields comprehensible rules with only slight degradation in test set prediction performance.