Mehdi Maadooliat

Assessing protein conformational sampling methods based on bivariate lag-distributions of backbone angles

Despite considerable progress in the past decades, protein structure prediction remains one of the major unsolved problems in computational biology. Angular-sampling-based methods have been extensively studied recently due to their ability to capture the continuous conformational space of protein structures. The literature has focused on using a variety of parametric models of the sequential dependencies between angle pairs along the protein chains. In this article, we present a thorough review of angular-sampling-based methods by assessing three main questions: What is the best distribution type to model the protein angles? What is a reasonable number of components in a mixture model that should be considered to accurately parameterize the joint distribution of the angles? and What is the order of the local sequence-structure dependency that should be considered by a prediction method? We assess the model fits for different methods using bivariate lag-distributions of the dihedral/planar angles. Moreover, the main information across the lags can be extracted using a technique called Lag singular value decomposition (LagSVD), which considers the joint distribution of the dihedral/planar angles over different lags using a nonparametric approach and monitors the behavior of the lag-distribution of the angles using singular value decomposition. As a result, we developed graphical tools and numerical measurements to compare and evaluate the performance of different model fits. Furthermore, we developed a web-tool (http://www.stat.tamu.edu/∼madoliat/LagSVD) that can be used to produce informative animations.

Collective estimation of multiple bivariate density functions with application to angular-sampling-based protein loop modeling

This article develops a method for simultaneous estimation of density functions for a collection of populations of protein backbone angle pairs using a data-driven, shared basis that is constructed by bivariate spline functions defined on a triangulation of the bivariate domain. The circular nature of angular data is taken into account by imposing appropriate smoothness constraints across boundaries of the triangles. Maximum penalized likelihood is used to fit the model and an alternating blockwise Newton-type algorithm is developed for computation. A simulation study shows that the collective estimation approach is statistically more efficient than estimating the densities individually. The proposed method was used to estimate neighbor-dependent distributions of protein backbone dihedral angles (i.e., Ramachandran distributions). The estimated distributions were applied to protein loop modeling, one of the most challenging open problems in protein structure prediction, by feeding them into an angular-sampling-based loop structure prediction framework. Our estimated distributions compared favorably to the Ramachandran distributions estimated by fitting a hierarchical Dirichlet process model; and in particular, our distributions showed significant improvements on the hard cases where existing methods do not work well.

Empirical Bayes and Hierarchical Bayes Estimation of Skew Normal Populations

We develop empirical and hierarchical Bayesian methodologies for the skew normal populations through the EM algorithm and the Gibbs sampler. A general concept of skewness to the normal distribution is considered throughout. Motivations are given for considering the skew normal population in applications, and an example is presented to demonstrate why the skew normal distribution is more applicable than the normal distribution for certain applications.

Skewed factor models using selection mechanisms

Traditional factor models explicitly or implicitly assume that the factors follow a multivariate normal distribution; that is, only moments up to order two are involved. However, it may happen in real data problems that the first two moments cannot explain the factors. Based on this motivation, here we devise three new skewed factor models, the skew-normal, the skew- t , and the generalized skew-normal factor models depending on a selection mechanism on the factors. The ECME algorithms are adopted to estimate related parameters for statistical inference. Monte Carlo simulations validate our new models and we demonstrate the need for skewed factor models using the classic open/closed book exam scores dataset.

Testing multiple hypotheses with skewed alternatives

In many practical cases of multiple hypothesis problems, it can be expected that the alternatives are not symmetrically distributed. If it is known a priori that the distributions of the alternatives are skewed, we show that this information yields high power procedures as compared to the procedures based on symmetric alternatives when testing multiple hypotheses. We propose a Bayesian decision theoretic rule for multiple directional hypothesis testing, when the alternatives are distributed as skewed, under a constraint on a mixed directional false discovery rate. We compare the proposed rule with a frequentists rule of Benjamini and Yekutieli (2005) using simulations. We apply our method to a well-studied HIV dataset.

Robust estimation of the correlation matrix of longitudinal data

We propose a double-robust procedure for modeling the correlation matrix of a longitudinal dataset. It is based on an alternative Cholesky decomposition of the form Σ=DLL⊤D where D is a diagonal matrix proportional to the square roots of the diagonal entries of Σ and L is a unit lower-triangular matrix determining solely the correlation matrix. The first robustness is with respect to model misspecification for the innovation variances in D, and the second is robustness to outliers in the data. The latter is handled using heavy-tailed multivariate t-distributions with unknown degrees of freedom. We develop a Fisher scoring algorithm for computing the maximum likelihood estimator of the parameters when the nonredundant and unconstrained entries of (L,D) are modeled parsimoniously using covariates. We compare our results with those based on the modified Cholesky decomposition of the form LD2L⊤ using simulations and a real dataset.

Preparing Family Caregivers to Recognize Delirium Symptoms in Older Adults After Elective Hip or Knee Arthroplasty

To test the feasibility of a telephone‐based intervention that prepares family caregivers to recognize delirium symptoms and how to communicate their observations to healthcare providers.

Protein Structure Classification and Loop Modeling Using Multiple Ramachandran Distributions

Recently, the study of protein structures using angular representations has attracted much attention among structural biologists. The main challenge is how to efficiently model the continuous conformational space of the protein structures based on the differences and similarities between different Ramachandran plots. Despite the presence of statistical methods for modeling angular data of proteins, there is still a substantial need for more sophisticated and faster statistical tools to model the large-scale circular datasets. To address this need, we have developed a nonparametric method for collective estimation of multiple bivariate density functions for a collection of populations of protein backbone angles. The proposed method takes into account the circular nature of the angular data using trigonometric spline which is more efficient compared to existing methods. This collective density estimation approach is widely applicable when there is a need to estimate multiple density functions from different populations with common features. Moreover, the coefficients of adaptive basis expansion for the fitted densities provide a low-dimensional representation that is useful for visualization, clustering, and classification of the densities. The proposed method provides a novel and unique perspective to two important and challenging problems in protein structure research: structure-based protein classification and angular-sampling-based protein loop structure prediction.

The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem

Several important and fundamental aspects of disease genetics models have yet to be described. One such property is the relationship of disease association statistics at a marker site closely linked to a disease causing site. A complete description of this two-locus system is of particular importance to experimental efforts to fine map association signals for complex diseases. Here, we present a simple relationship between disease association statistics and the decline of linkage disequilibrium from a causal site. Specifically, the ratio of Chi-square disease association statistics at a marker site and causal site is equivalent to the standard measure of pairwise linkage disequilibrium, r2. A complete derivation of this relationship from a general disease model is shown. Quite interestingly, this relationship holds across all modes of inheritance. Extensive Monte Carlo simulations using a disease genetics model applied to chromosomes subjected to a standard model of recombination are employed to better understand the variation around this fine mapping theorem due to sampling effects. We also use this relationship to provide a framework for estimating properties of a non-interrogated causal site using data at closely linked markers. Lastly, we apply this way of examining association data from high-density genotyping in a large, publicly-available data set investigating extreme BMI. We anticipate that understanding the patterns of disease association decay with declining linkage disequilibrium from a causal site will enable more powerful fine mapping methods and provide new avenues for identifying causal sites/genes from fine-mapping studies.

Remarks on characterizations of Malinowska and Szynal

The problem of characterizing a distribution is an important problem which has recently attracted the attention of many researchers. Thus, various characterizations have been established in many different directions. An investigator will be vitally interested to know if their model fits the requirements of a particular distribution. To this end, one will depend on the characterizations of this distribution which provide conditions under which the underlying distribution is indeed that particular distribution. In this work, several characterizations of Malinowska and Szynal (2008) for certain general classes of distributions are revisited and simpler proofs of them are presented. These characterizations are not based on conditional expectation of the kth lower record values (as in Malinowska and Szynal), they are based on: (i) simple truncated moments of the random variable, (ii) hazard function.