BackgroundPLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for faster and scalable implementations of key functions, such as logistic regression, linkage disequilibrium estimation, and genomic distance evaluation. In addition, GWAS and population-genetic data now frequently contain genotype likelihoods, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1’s primary data format.FindingsTo address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, -time/constant-space Hardy-Weinberg equilibrium and Fisher’s exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. We have also developed an extension to the data format which adds low-overhead support for genotype likelihoods, phase, multiallelic variants, and reference vs. alternate alleles, which is the basis of our planned second release (PLINK 2.0).ConclusionsThe second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.Electronic supplementary materialThe online version of this article (doi:10.1186/s13742-015-0047-8) contains supplementary material, which is available to authorized users.

Obesity interventions can result in weight loss, but accurate prediction of the bodyweight time course requires properly accounting for dynamic energy imbalances. In this report, we describe a mathematical modelling approach to adult human metabolism that simulates energy expenditure adaptations during weight loss. We also present a web-based simulator for prediction of weight change dynamics. We show that the bodyweight response to a change of energy intake is slow, with half times of about 1 year. Furthermore, adults with greater adiposity have a larger expected weight loss for the same change of energy intake, and to reach their steady-state weight will take longer than it would for those with less initial body fat. Using a population-averaged model, we calculated the energy-balance dynamics corresponding to the development of the US adult obesity epidemic. A small persistent average daily energy imbalance gap between intake and expenditure of about 30 kJ per day underlies the observed average weight gain. However, energy intake must have risen to keep pace with increased expenditure associated with increased weight. The average increase of energy intake needed to sustain the increased weight (the maintenance energy gap) has amounted to about 0·9 MJ per day and quantifies the public health challenge to reverse the obesity epidemic.

Stochastic resonance (SR) is a phenomenon wherein the response of a nonlinear system to a weak periodic input signal is optimized by the presence of a particular, non-zero level of noise. SR has been proposed as a means for improving signal detection in a wide variety of systems, including superconducting quantum interference devices, and may be used in some natural systems such as sensory neurons. But for SR to be effective in a single-unit system (such as a sensory neuron or a single ion channel), the optimal intensity of the noise must be adjusted as the nature of the signal to be detected changes. This has been thought to impose a limitation on the practical and natural uses of SR. Here we show that the ability of a summing network of excitable units to detect a range of weak (sub-threshold) signals (either periodic or aperiodic) can be optimized by a fixed level of noise, irrespective of the nature of the input signal. We also show that this noise does not significantly degrade the ability of the network to detect suprathreshold signals. Thus, large nonlinear networks do not suffer from the limitations of SR in single units, and might be able to use a single noise level, such as that provided by the intrinsic noise of the individual components, to enhance the system's sensitivity to weak inputs. This suggests a functional role for neuronal noise in sensory systems.