Does pathway analysis make it easier for common variants to tag rare ones?

Analyzing sequencing data is difficult because of the low frequency of rare variants, which may result in low power to detect associations. We consider pathway analysis to detect multiple common and rare variants jointly and to investigate whether analysis at the pathway level provides an alternative strategy for identifying susceptibility genes. Available pathway analysis methods for data from genome-wide association studies might not be efficient because these methods are designed to detect common variants. Here, we investigate the performance of several existing pathway analysis methods for sequencing data. In particular, we consider the global test, which does not consider linkage disequilibrium between the variants in a gene. We improve the performance of the global test by assigning larger weights to rare variants, as proposed in the weighted-sum approach. Our conclusion is that straightforward application of pathway analysis is not satisfactory; hence, when common and rare variants are jointly analyzed, larger weights should be assigned to rare variants

Survival analysis with delayed entry in selected families with application to human longevity

In the field of aging research, family-based sampling study designs are commonly used to study the lifespans of long-lived family members. However, the specific sampling procedure should be carefully taken into account in order to avoid biases. This work is motivated by the Leiden Longevity Study, a family-based cohort of long-lived siblings. Families were invited to participate in the study if at least two siblings were ‘long-lived’, where ‘long-lived’ meant being older than 89 years for men or older than 91 years for women. As a result, more than 400 families were included in the study and followed for around 10 years. For estimation of marker-specific survival probabilities and correlations among life times of family members, delayed entry due to outcome-dependent sampling mechanisms has to be taken into account. We consider shared frailty models to model left-truncated correlated survival data. The treatment of left truncation in shared frailty models is still an open issue and the literature on this topic is scarce. We show that the current approaches provide, in general, biased estimates and we propose a new method to tackle this selection problem by applying a correction on the likelihood estimation by means of inverse probability weighting at the family level

Sequential double cross-validation for assessment of added predictive ability in high-dimensional omic applications

Enriching existing predictive models with new biomolecular markers is an important task in the new multi-omic era. Clinical studies increasingly include new sets of omic measurements which may prove their added value in terms of predictive performance. We introduce a two-step approach for the assessment of the added predictive ability of omic predictors, based on sequential double cross-validation and regularized regression models. We propose several performance indices to summarize the two-stage prediction procedure and a permutation test to formally assess the added predictive value of a second omic set of predictors over a primary omic source. The performance of the test is investigated through simulations. We illustrate the new method through the systematic assessment and comparison of the performance of transcriptomics and metabolomics sources in the prediction of body mass index (BMI) using longitudinal data from the Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) study, a population-based cohort from Finland

Moduli spaces of toric manifolds

We construct a distance on the moduli space of symplectic toric manifolds of dimension four. Then we study some basic topological properties of this space, in particular, path-connectedness, compactness, and completeness. The construction of the distance is related to the Duistermaat-Heckman measure and the Hausdorff metric. While the moduli space, its topology and metric, may be constructed in any dimension, the tools we use in the proofs are four-dimensional, and hence so is our main result.Comment: To appear in Geometriae Dedicata, minor changes to previous version, 19 pages, 6 figure

A fixed point formula for the index of multi-centered N=2 black holes

We propose a formula for computing the (moduli-dependent) contribution of multi-centered solutions to the total BPS index in terms of the (moduli-independent) indices associated to single-centered solutions. The main tool in our analysis is the computation of the refined index Tr(-y)^{2J_3} of configurational degrees of freedom of multi-centered BPS black hole solutions in N=2 supergravity by localization methods. When the charges carried by the centers do not allow for scaling solutions (i.e. solutions where a subset of the centers can come arbitrarily close to each other), the phase space of classical BPS solutions is compact and the refined index localizes to a finite set of isolated fixed points under rotations, corresponding to collinear solutions. When the charges allow for scaling solutions, the phase space is non-compact but appears to admit a compactification with finite volume and additional non-isolated fixed points. We give a prescription for determining the contributions of these fixed submanifolds by means of a `minimal modification hypothesis', which we prove in the special case of dipole halo configurations.Comment: 61 pages, 3 figure

Estimating Constraints for Protection Factors from HDX-MS Data

Hydrogen/deuterium exchange monitored by mass spectrometry is a promising technique for rapidly fingerprinting structural and dynamical properties of proteins. The time-dependent change in the mass of any fragment of the polypeptide chain depends uniquely on the rate of exchange of its amide hydrogens, but determining the latter from the former is generally not possible. Here, we show that, if time-resolved measurements are available for a number of overlapping peptides that cover the whole sequence, rate constants for each amide hydrogen exchange (or equivalently, their protection factors) may be extracted and the uniqueness of the solutions obtained depending on the degree of peptide overlap. However, in most cases, the solution is not unique, and multiple alternatives must be considered. We provide a statistical method that clusters the solutions to further reduce their number. Such analysis always provides meaningful constraints on protection factors and can be used in situations in which obtaining more refined experimental data is impractical. It also provides a systematic way to improve data collection strategies to obtain unambiguous information at single-residue level (e.g., for assessing protein structure predictions at atomistic level)

Direct Detection of Electroweak-Interacting Dark Matter

Assuming that the lightest neutral component in an SU(2)L gauge multiplet is the main ingredient of dark matter in the universe, we calculate the elastic scattering cross section of the dark matter with nucleon, which is an important quantity for the direct detection experiments. When the dark matter is a real scalar or a Majorana fermion which has only electroweak gauge interactions, the scattering with quarks and gluon are induced through one- and two-loop quantum processes, respectively, and both of them give rise to comparable contributions to the elastic scattering cross section. We evaluate all of the contributions at the leading order and find that there is an accidental cancellation among them. As a result, the spin-independent cross section is found to be O(10^-(46-48)) cm^2, which is far below the current experimental bounds.Comment: 19 pages, 7 figures, published versio