Accelerating epistasis analysis in human genetics with consumer graphics hardware

BACKGROUND: Human geneticists are now capable of measuring more than one million DNA sequence variations from across the human genome. The new challenge is to develop computationally feasible methods capable of analyzing these data for associations with common human disease, particularly in the context of epistasis. Epistasis describes the situation where multiple genes interact in a complex non-linear manner to determine an individual's disease risk and is thought to be ubiquitous for common diseases. Multifactor Dimensionality Reduction (MDR) is an algorithm capable of detecting epistasis. An exhaustive analysis with MDR is often computationally expensive, particularly for high order interactions. This challenge has previously been met with parallel computation and expensive hardware. The option we examine here exploits commodity hardware designed for computer graphics. In modern computers Graphics Processing Units (GPUs) have more memory bandwidth and computational capability than Central Processing Units (CPUs) and are well suited to this problem. Advances in the video game industry have led to an economy of scale creating a situation where these powerful components are readily available at very low cost. Here we implement and evaluate the performance of the MDR algorithm on GPUs. Of primary interest are the time required for an epistasis analysis and the price to performance ratio of available solutions. FINDINGS: We found that using MDR on GPUs consistently increased performance per machine over both a feature rich Java software package and a C++ cluster implementation. The performance of a GPU workstation running a GPU implementation reduces computation time by a factor of 160 compared to an 8-core workstation running the Java implementation on CPUs. This GPU workstation performs similarly to 150 cores running an optimized C++ implementation on a Beowulf cluster. Furthermore this GPU system provides extremely cost effective performance while leaving the CPU available for other tasks. The GPU workstation containing three GPUs costs $2000 while obtaining similar performance on a Beowulf cluster requires 150 CPU cores which, including the added infrastructure and support cost of the cluster system, cost approximately$82,500. CONCLUSION: Graphics hardware based computing provides a cost effective means to perform genetic analysis of epistasis using MDR on large datasets without the infrastructure of a computing cluster

Inner-shelf circulation and sediment dynamics on a series of shoreface-connected ridges offshore of Fire Island, NY

Locations along the inner-continental shelf offshore of Fire Island, NY, are characterized by a series of shoreface-connected ridges (SFCRs). These sand ridges have approximate dimensions of 10 km in length, 3 km spacing, and up to similar to 8 m ridge to trough relief and are oriented obliquely at approximately 30 degrees clockwise from the coastline. Stability analysis from previous studies explains how sand ridges such as these could be formed and maintained by storm-driven flows directed alongshore with a key maintenance mechanism of offshore deflected flows over ridge crests and onshore in the troughs. We examine these processes both with a limited set of idealized numerical simulations and analysis of observational data. Model results confirm that alongshore flows over the SFCRs exhibit offshore veering of currents over the ridge crests and onshore-directed flows in the troughs, and demonstrate the opposite circulation pattern for a reverse wind. To further investigate these maintenance processes, oceanographic instruments were deployed at seven sites on the SFCRs offshore of Fire Island to measure water levels, ocean currents, waves, suspended sediment concentrations, and bottom stresses from January to April 2012. Data analysis reveals that during storms with winds from the northeast, the processes of offshore deflection of currents over ridge crests and onshore in the troughs were observed, and during storm events with winds from the southwest, a reverse flow pattern over the ridges occurred. Computations of suspended sediment fluxes identify periods that are consistent with SFCR maintenance mechanisms. Alongshore winds from the northeast drove fluxes offshore on the ridge crest and onshore in the trough that would tend to promote ridge maintenance. However, alongshore winds from the southwest drove opposite circulations. The wind fields are related to different storm types that occur in the region (low-pressure systems, cold fronts, and warm fronts). From the limited data set, we identify that low-pressure systems drive sediment fluxes that tend to promote stability and maintain the SFCRs while cold front type storms appear to drive circulations that are in the opposite sense and may not be a supporting mechanism for ridge maintenance

A discrete geometric model of concurrent program execution

A trace of the execution of a concurrent object-oriented program can be displayed in two-dimensions as a diagram of a non-metric finite geometry. The actions of a programs are represented by points, its objects and threads by vertical lines, its transactions by horizontal lines, its communications and resource sharing by sloping arrows, and its partial traces by rectangular figures. We prove informally that the geometry satisfies the laws of Concurrent Kleene Algebra (CKA); these describe and justify the interleaved implementation of multithreaded programs on computer systems with a lesser number of concurrent processors. More familiar forms of semantics (e.g., verification-oriented and operational) can be derived from CKA. Programs are represented as sets of all their possible traces of execution, and non-determinism is introduced as union of these sets. The geometry is extended to multiple levels of abstraction and granularity; a method call at a higher level can be modelled by a specification of the method body, which is implemented at a lower level. The final section describes how the axioms and definitions of the geometry have been encoded in the interactive proof tool Isabelle, and reports on progress towards automatic checking of the proofs in the paper

Diabetes status and post-load plasma glucose concentration in relation to site-specific cancer mortality: findings from the original Whitehall study

ObjectiveWhile several studies have reported on the relation of diabetes status with pancreatic cancer risk, the predictive value of this disorder for other malignancies is unclear. Methods: The Whitehall study, a 25year follow-up for mortality experience of 18,006 men with data on post-challenge blood glucose and self-reported diabetes, allowed us to address these issues. Results: There were 2158 cancer deaths at follow-up. Of the 15 cancer outcomes, diabetes status was positively associated with mortality from carcinoma of the pancreas and liver, while the relationship with lung cancer was inverse, after controlling for a range of potential covariates and mediators which included obesity and socioeconomic position. After excluding deaths occurring in the first 10years of follow-up to examine the effect of reverse causality, the magnitude of the relationships for carcinoma of the pancreas and lung was little altered, while for liver cancer it was markedly attenuated. Conclusions: In the present study, diabetes status was related to pancreatic, liver, and lung cancer risk. Cohorts with serially collected data on blood glucose and covariates are required to further examine this area

Traditional Cantonese diet and nasopharyngeal carcinoma risk: a large-scale case-control study in Guangdong, China

<p>Abstract</p> <p>Background</p> <p>Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but is a common malignancy in southern China, especially in Guangdong. Dietary habit is regarded as an important modifier of NPC risk in several endemic areas and may partially explain the geographic distribution of NPC incidence. In China, rapid economic development during the past few decades has changed the predominant lifestyle and dietary habits of the Chinese considerably, requiring a reassessment of diet and its potential influence on NPC risk in this NPC-endemic area.</p> <p>Methods</p> <p>To evaluate the association between dietary factors and NPC risk in Guangdong, China, a large-scale, hospital-based case-control study was conducted. 1387 eligible cases and 1459 frequency matched controls were recruited. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated using a logistic regression model, adjusting for age, sex, education, dialect, and habitation household type.</p> <p>Results</p> <p>Observations made include the following: 1) consumption of canton-style salted fish, preserved vegetables and preserved/cured meat were significantly associated with increased risk of NPC, with enhanced odds ratios (OR) of 2.45 (95% CI: 2.03-2.94), 3.17(95% CI: 2.68-3.77) and 2.09 (95% CI: 1.22-3.60) respectively in the highest intake frequency stratum during childhood; 2) consumption of fresh fruit was associated with reduced risk with a dose-dependent relationship (p = 0.001); and 3) consumption of Canton-style herbal tea and herbal slow-cooked soup was associated with decreased risk, with ORs of 0.84 (95% CI: 0.68-1.03) and 0.58 (95% CI: 0.47-0.72) respectively in the highest intake frequency stratum. In multivariate analyses, these associations remained significant.</p> <p>Conclusions</p> <p>It can be inferred that previously established dietary risk factors in the Cantonese population are still stable and have contributed to the incidence of NPC.</p

Semi-sparse PCA

It is well-known that the classical exploratory factor analysis (EFA) of data with more observations than variables has several types of indeterminacy. We study the factor indeterminacy and show some new aspects of this problem by considering EFA as a specific data matrix decomposition. We adopt a new approach to the EFA estimation and achieve a new characterization of the factor indeterminacy problem. A new alternative model is proposed, which gives determinate factors and can be seen as a semi-sparse principal component analysis (PCA). An alternating algorithm is developed, where in each step a Procrustes problem is solved. It is demonstrated that the new model/algorithm can act as a specific sparse PCA and as a low-rank-plus-sparse matrix decomposition. Numerical examples with several large data sets illustrate the versatility of the new model, and the performance and behaviour of its algorithmic implementation

Terahertz underdamped vibrational motion governs protein-ligand binding in solution

Low-frequency collective vibrational modes in proteins have been proposed as being responsible for efficiently directing biochemical reactions and biological energy transport. However, evidence of the existence of delocalized vibrational modes is scarce and proof of their involvement in biological function absent. Here we apply extremely sensitive femtosecond optical Kerr-effect spectroscopy to study the depolarized Raman spectra of lysozyme and its complex with the inhibitor triacetylchitotriose in solution. Underdamped delocalized vibrational modes in the terahertz frequency domain are identified and shown to blue-shift and strengthen upon inhibitor binding. This demonstrates that the ligand-binding coordinate in proteins is underdamped and not simply solvent-controlled as previously assumed. The presence of such underdamped delocalized modes in proteins may have significant implications for the understanding of the efficiency of ligand binding and protein–molecule interactions, and has wider implications for biochemical reactivity and biological function

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of Intermediate Care Clinics for Diabetes (ICCD) : study protocol for a randomized controlled trial

Background World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. Methods/Design This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or Control group: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients

Poor body condition is associated with lower hippocampal plasticity and higher gut methanogen abundance in adult laying hens from two housing systems

It is still unclear which commercial housing system provides the best quality of life for laying hens. In addition, there are large individual differences in stress levels within a system. Hippocampal neurogenesis or plasticity may provide an integrated biomarker of the stressors experienced by an individual. We selected 12 adult hens each with good and poor body condition (based on body size, degree of feather cover and redness of the comb) from a multi-tier free range system containing H&N strain hens, and from an enriched cage system containing Hy-Line hens (n = 48 total). Immature neurons expressing doublecortin (DCX) were quantified in the hippocampus, contents of the caecal microbiome were sequenced, and expression of inflammatory cytokines was measured in the spleen. DCX+ cell densities did not differ between the housing systems. In both systems, poor condition hens had lower DCX+ cell densities, exhibited elevated splenic expression of interleukin-6 (IL6) mRNA, and had a higher relative caecal abundance of methanogenic archea Methanomethylophilaceae. The findings suggest poor body condition is an indicator that individual hens have experienced a comparatively greater degree of cumulative chronic stress, and that a survey of the proportion of hens with poor body conditions might be one way to evaluate the impact of housing systems on hen welfare