Novartis

Abstract: We present the derivation of a new molecular mechanical force field for simulating the structures, conformational energies, and interaction energies of proteins, nucleic acids, and many related organic molecules in condensed phases. This effective two-body force field is the successor to the Weiner et al. force field and was developed with some of the same philosophies, such as the use of a simple diagonal potential function and electrostatic potential fit atom centered charges. The need for a 10-12 function for representing hydrogen bonds is no longer necessary due to the improved performance of the new charge model and new van der Waals parameters. These new charges are determined using a 6-31G* basis set and restrained electrostatic potential (RESP) fitting and have been shown to reproduce interaction energies, free energies of solvation, and conformational energies of simple small molecules to a good degree of accuracy. Furthermore, the new RESP charges exhibit less variability as a function of the molecular conformation used in the charge determination. The new van der Waals parameters have been derived from liquid simulations and include hydrogen parameters which take into account the effects of any geminal electronegative atoms. The bonded parameters developed by Weiner et al. were modified as necessary to reproduce experimental vibrational frequencies and structures. Most of the simple dihedral parameters have been retained from Weiner et al., but a complex set of 4 and yj parameters which do a good job of reproducing the energies of the low-energy conformations of glycyl and alanyl dipeptides has been developed for the peptide backbone.

Abstract: We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching.

Abstract: Simultaneous inference is a common problem in many areas of application. If multiple null hypotheses are tested simultaneously, the probability of rejecting erroneously at least one of them increases beyond the pre-specified significance level. Simultaneous inference procedures have to be used which adjust for multiplicity and thus control the overall type I error rate. In this paper we describe simultaneous inference procedures in general parametric models, where the experimental questions are specified through a linear combination of elemental model parameters. The framework described here is quite general and extends the canonical theory of multiple comparison procedures in ANOVA models to linear regression problems, generalized linear models, linear mixed effects models, the Cox model, robust linear models, etc. Several examples using a variety of different statistical models illustrate the breadth

Abstract: INTRODUCING MARKOV CHAIN MONTE CARLO Introduction The Problem Markov Chain Monte Carlo Implementation Discussion HEPATITIS B: A CASE STUDY IN MCMC METHODS Introduction Hepatitis B Immunization Modelling Fitting a Model Using Gibbs Sampling Model Elaboration Conclusion MARKOV CHAIN CONCEPTS RELATED TO SAMPLING ALGORITHMS Markov Chains Rates of Convergence Estimation The Gibbs Sampler and Metropolis-Hastings Algorithm INTRODUCTION TO GENERAL STATE-SPACE MARKOV CHAIN THEORY Introduction Notation and Definitions Irreducibility, Recurrence, and Convergence Harris Recurrence Mixing Rates and Central Limit Theorems Regeneration Discussion FULL CONDITIONAL DISTRIBUTIONS Introduction Deriving Full Conditional Distributions Sampling from Full Conditional Distributions Discussion STRATEGIES FOR IMPROVING MCMC Introduction Reparameterization Random and Adaptive Direction Sampling Modifying the Stationary Distribution Methods Based on Continuous-Time Processes Discussion IMPLEMENTING MCMC Introduction Determining the Number of Iterations Software and Implementation Output Analysis Generic Metropolis Algorithms Discussion INFERENCE AND MONITORING CONVERGENCE Difficulties in Inference from Markov Chain Simulation The Risk of Undiagnosed Slow Convergence Multiple Sequences and Overdispersed Starting Points Monitoring Convergence Using Simulation Output Output Analysis for Inference Output Analysis for Improving Efficiency MODEL DETERMINATION USING SAMPLING-BASED METHODS Introduction Classical Approaches The Bayesian Perspective and the Bayes Factor Alternative Predictive Distributions How to Use Predictive Distributions Computational Issues An Example Discussion HYPOTHESIS TESTING AND MODEL SELECTION Introduction Uses of Bayes Factors Marginal Likelihood Estimation by Importance Sampling Marginal Likelihood Estimation Using Maximum Likelihood Application: How Many Components in a Mixture? Discussion Appendix: S-PLUS Code for the Laplace-Metropolis Estimator MODEL CHECKING AND MODEL IMPROVEMENT Introduction Model Checking Using Posterior Predictive Simulation Model Improvement via Expansion Example: Hierarchical Mixture Modelling of Reaction Times STOCHASTIC SEARCH VARIABLE SELECTION Introduction A Hierarchical Bayesian Model for Variable Selection Searching the Posterior by Gibbs Sampling Extensions Constructing Stock Portfolios With SSVS Discussion BAYESIAN MODEL COMPARISON VIA JUMP DIFFUSIONS Introduction Model Choice Jump-Diffusion Sampling Mixture Deconvolution Object Recognition Variable Selection Change-Point Identification Conclusions ESTIMATION AND OPTIMIZATION OF FUNCTIONS Non-Bayesian Applications of MCMC Monte Carlo Optimization Monte Carlo Likelihood Analysis Normalizing-Constant Families Missing Data Decision Theory Which Sampling Distribution? Importance Sampling Discussion STOCHASTIC EM: METHOD AND APPLICATION Introduction The EM Algorithm The Stochastic EM Algorithm Examples GENERALIZED LINEAR MIXED MODELS Introduction Generalized Linear Models (GLMs) Bayesian Estimation of GLMs Gibbs Sampling for GLMs Generalized Linear Mixed Models (GLMMs) Specification of Random-Effect Distributions Hyperpriors and the Estimation of Hyperparameters Some Examples Discussion HIERARCHICAL LONGITUDINAL MODELLING Introduction Clinical Background Model Detail and MCMC Implementation Results Summary and Discussion MEDICAL MONITORING Introduction Modelling Medical Monitoring Computing Posterior Distributions Forecasting Model Criticism Illustrative Application Discussion MCMC FOR NONLINEAR HIERARCHICAL MODELS Introduction Implementing MCMC Comparison of Strategies A Case Study from Pharmacokinetics-Pharmacodynamics Extensions and Discussion BAYESIAN MAPPING OF DISEASE Introduction Hypotheses and Notation Maximum Likelihood Estimation of Relative Risks Hierarchical Bayesian Model of Relative Risks Empirical Bayes Estimation of Relative Risks Fully Bayesian Estimation of Relative Risks Discussion MCMC IN IMAGE ANALYSIS Introduction The Relevance of MCMC to Image Analysis Image Models at Different Levels Methodological Innovations in MCMC Stimulated by Imaging Discussion MEASUREMENT ERROR Introduction Conditional-Independence Modelling Illustrative examples Discussion GIBBS SAMPLING METHODS IN GENETICS Introduction Standard Methods in Genetics Gibbs Sampling Approaches MCMC Maximum Likelihood Application to a Family Study of Breast Cancer Conclusions MIXTURES OF DISTRIBUTIONS: INFERENCE AND ESTIMATION Introduction The Missing Data Structure Gibbs Sampling Implementation Convergence of the Algorithm Testing for Mixtures Infinite Mixtures and Other Extensions AN ARCHAEOLOGICAL EXAMPLE: RADIOCARBON DATING Introduction Background to Radiocarbon Dating Archaeological Problems and Questions Illustrative Examples Discussion Index

Abstract: Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.