Exploring novel designs of NLP solvers: Architecture and Implementation of WORHP

Mathematical Optimization in general and Nonlinear Programming in particular, are applied by many scientific disciplines, such as the automotive sector, the aerospace industry, or the space agencies. With some established NLP solvers having been available for decades, and with the mathematical community being rather conservative in this respect, many of their programming standards are severely outdated. It is safe to assume that such usability shortcomings impede the wider use of NLP methods; a representative example is the use of static workspaces by legacy FORTRAN codes. This dissertation gives an account of the construction of the European NLP solver WORHP by using and combining software standards and techniques that have not previously been applied to mathematical software to this extent. Examples include automatic code generation, a consistent reverse communication architecture and the elimination of static workspaces. The result is a novel, industrial-grade NLP solver that overcomes many technical weaknesses of established NLP solvers and other mathematical software

Multiethnic Exome-Wide Association Study of Subclinical AtherosclerosisCLINICAL PERSPECTIVE

The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD

Neuartige Design-Ansätze für NLP-Solver: Architektur und Implementierung von WORHP

Mathematical Optimization in general and Nonlinear Programming in particular, are applied by many scientific disciplines, such as the automotive sector, the aerospace industry, or the space agencies. With some established NLP solvers having been available for decades, and with the mathematical community being rather conservative in this respect, many of their programming standards are severely outdated. It is safe to assume that such usability shortcomings impede the wider use of NLP methods; a representative example is the use of static workspaces by legacy FORTRAN codes. This dissertation gives an account of the construction of the European NLP solver WORHP by using and combining software standards and techniques that have not previously been applied to mathematical software to this extent. Examples include automatic code generation, a consistent reverse communication architecture and the elimination of static workspaces. The result is a novel, industrial-grade NLP solver that overcomes many technical weaknesses of established NLP solvers and other mathematical software

Fine-mapping the genetic basis of CRP regulation in African Americans: a Bayesian approach.

Basal levels of C-reactive protein (CRP) have been associated with disease, particularly future cardiovascular events. Twin studies estimate 50% CRP heritability, so the identification of genetic variants influencing CRP expression is important. Existing studies in populations of European ancestry have identified numerous cis-acting variants but leave significant ambiguity over the identity of the key functional polymorphisms. We addressed this issue by typing a dense map of CRP single-nucleotide polymorphisms (SNPs), and quantifying serum CRP in 594 unrelated African Americans. We used Bayesian model choice analysis to select the combination of SNPs best explaining basal CRP and found strong support for triallelic rs3091244 alone, with the T allele acting in an additive manner (Bayes factor > 100 vs. null model), with additional support for a model incorporating both rs3091244 and rs12728740. Admixture analysis suggested SNP rs12728740 segregated with haplotypes predicted to be of recent European origin. Using a cladistic approach we confirmed the importance of rs3091244(T) by demonstrating a significant partition of haplotype effect based on the rs3091244(C/T) mutation (F = 8.91, P = 0.006). We argue that weaker linkage disequilibrium across the African American CRP locus compared with Europeans has allowed us to establish an unambiguous functional role for rs3091244(T), while also recognising the potential for additional functional mutations present in the European genome

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans