Estimation of Selection Parameters using Multi‐generation Cytonuclear Data

We have developed an approximate maximum likelihood framework for the problem of estimating the selection coefficients in a simple fertility selection model via random union of zygotes. We consider a sampling scheme where a random sample from each (discrete) generation of a population observed over several generations is collected and genotyped based on one nuclear locus and a cytonuclear locus, simultaneously. Simulation results show excellent small sample performance of the resulting approximate MLE. Asymptotic variance‐covariance matrix of our estimator is also obtained. We further show that these estimates can be used to obtain simple test statistics for testing various types of selection hypotheses including a test of neutrality.     

On a Simple Procedure of Inclusion Probability Proportional to Sizes (IPPS) Sampling

A simple method of inclusion probability proportional to sizes is proposed for samples of size three units. It is shown that the variance of the HORVITZ -THOMPSON estimator based on the proposed sampling scheme is uniformly smaller than that of the customary estimator used in the probability proportional to sizes with replacement sampling. Further, its performance over RAO -HARTLEY -COCHRAN and SAMPFORD sampling schemes has been studied empirically for some of the natural populations.     

Extrapolation of urn models via poissonization: accurate measurements of the microbial unknown

The availability of high-throughput parallel methods for sequencing microbial communities is increasing our knowledge of the microbial world at an unprecedented rate. Though most attention has focused on determining lower-bounds on the α-diversity i.e. the total number of different species present in the environment, tight bounds on this quantity may be highly uncertain because a small fraction of the environment could be composed of a vast number of different species. To better assess what remains unknown, we propose instead to predict the fraction of the environment that belongs to unsampled classes. Modeling samples as draws with replacement of colored balls from an urn with an unknown composition, and under the sole assumption that there are still undiscovered species, we show that conditionally unbiased predictors and exact prediction intervals (of constant length in logarithmic scale) are possible for the fraction of the environment that belongs to unsampled classes. Our predictions are based on a poissonization argument, which we have implemented in what we call the Embedding algorithm. In fixed i.e. non-randomized sample sizes, the algorithm leads to very accurate predictions on a sub-sample of the original sample. We quantify the effect of fixed sample sizes on our prediction intervals and test our methods and others found in the literature against simulated environments, which we devise taking into account datasets from a human-gut and -hand microbiota. Our methodology applies to any dataset that can be conceptualized as a sample with replacement from an urn. In particular, it could be applied, for example, to quantify the proportion of all the unseen solutions to a binding site problem in a random RNA pool, or to reassess the surveillance of a certain terrorist group, predicting the conditional probability that it deploys a new tactic in a next attack.     

Borrowing information across genes and experiments for improved error variance estimation in microarray data analysis

Statistical inference for microarray experiments usually involves the estimation of error variance for each gene. Because the sample size available for each gene is often low, the usual unbiased estimator of the error variance can be unreliable. Shrinkage methods, including empirical Bayes approaches that borrow information across genes to produce more stable estimates, have been developed in recent years. Because the same microarray platform is often used for at least several experiments to study similar biological systems, there is an opportunity to improve variance estimation further by borrowing information not only across genes but also across experiments. We propose a lognormal model for error variances that involves random gene effects and random experiment effects. Based on the model, we develop an empirical Bayes estimator of the error variance for each combination of gene and experiment and call this estimator BAGE because information is Borrowed Across Genes and Experiments. A permutation strategy is used to make inference about the differential expression status of each gene. Simulation studies with data generated from different probability models and real microarray data show that our method outperforms existing approaches.     

A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB

The discrete coefficient of determination (CoD) measures the nonlinear interaction between discrete predictor and target variables and has had far-reaching applications in Genomic Signal Processing. Previous work has addressed the inference of the discrete CoD using classical parametric and nonparametric approaches. In this paper, we introduce a Bayesian framework for the inference of the discrete CoD. We derive analytically the optimal minimum mean-square error (MMSE) CoD estimator, as well as a CoD estimator based on the Optimal Bayesian Predictor (OBP). For the latter estimator, exact expressions for its bias, variance, and root-mean-square (RMS) are given. The accuracy of both Bayesian CoD estimators with non-informative and informative priors, under fixed or random parameters, is studied via analytical and numerical approaches. We also demonstrate the application of the proposed Bayesian approach in the inference of gene regulatory networks, using gene-expression data from a previously published study on metastatic melanoma.     

Five Confidence Intervals of the Closed Population Size in the Capture‐recapture Problem under Inverse Sampling with Replacement

In the capture‐recapture problem for two independent samples, the traditional estimator, calculated as the product of the two sample sizes divided by the number of sampled subjects appearing commonly in both samples, is well known to be a biased estimator of the population size and have no finite variance under direct or binomial sampling. To alleviate these theoretical limitations, the inverse sampling, in which we continue sampling subjects in the second sample until we obtain a desired number of marked subjects who appeared in the first sample, has been proposed elsewhere. In this paper, we consider five interval estimators of the population size, including the most commonly‐used interval estimator using Wald's statistic, the interval estimator using the logarithmic transformation, the interval estimator derived from a quadratic equation developed here, the interval estimator using the χ²‐approximation, and the interval estimator based on the exact negative binomial distribution. To evaluate and compare the finite sample performance of these estimators, we employ Monte Carlo simulation to calculate the coverage probability and the standardized average length of the resulting confidence intervals in a variety of situations. To study the location of these interval estimators, we calculate the non‐coverage probability in the two tails of the confidence intervals. Finally, we briefly discuss the optimal sample size determination for a given precision to minimize the expected total cost. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Assessment of agreement under nonstandard conditions using regression models for mean and variance

The total deviation index of Lin and Lin et al. is an intuitive approach for the assessment of agreement between two methods of measurement. It assumes that the differences of the paired measurements are a random sample from a normal distribution and works essentially by constructing a probability content tolerance interval for this distribution. We generalize this approach to the case when differences may not have identical distributions -- a common scenario in applications. In particular, we use the regression approach to model the mean and the variance of differences as functions of observed values of the average of the paired measurements, and describe two methods based on asymptotic theory of maximum likelihood estimators for constructing a simultaneous probability content tolerance band. The first method uses bootstrap to approximate the critical point and the second method is an analytical approximation. Simulation shows that the first method works well for sample sizes as small as 30 and the second method is preferable for large sample sizes. We also extend the methodology for the case when the mean function is modeled using penalized splines via a mixed model representation. Two real data applications are presented.     

A Note on RAO's Inclusion Probability Proportional to size Sampling Scheme

A sufficient condition that the variance of HORVITZ -THOMPSON estimator for RAO 's (1965) inclusion probability proportional to sizes sampling scheme of selecting two units is uniformly smaller than that of RAO , HARTLEY and COCHRAN (1962) estimator has been obtained.     

Point Estimation on Relative Risk under Inverse Sampling

When the underlying disease is rare, to control the coefficient of variation for the sample proportion of cases, we may wish to apply inverse sampling. In this paper, we derive the uniformly minimum variance unbiased estimator (UMVUE) of relative risk and its variance in closed form under inverse sampling. On the basis of a Monte Carlo simulation, we demonstrate that using the UMVUE of relative risk can substantially reduce the mean-squared-error of using the maximum likelihood estimator, especially when the number of index cases in both comparison samples is small. For a given fixed total cost, we include a program that can be used to find the optimal allocation for the number of index cases to minimize the variance of the UMVUE as well.     

Bayesian Nonparametric Estimation of the Probability of Discovering New Species

We consider the problem of evaluating the probability of discoveringa certain number of new species in a new sample of populationunits, conditional on the number of species recorded in a basicsample. We use a Bayesian nonparametric approach. The differentspecies proportions are assumed to be random and the observationsfrom the population exchangeable. We provide a Bayesian estimator,under quadratic loss, for the probability of discovering newspecies which can be compared with well-known frequentist estimators.The results we obtain are illustrated through a numerical exampleand an application to a genomic dataset concerning the discoveryof new genes by sequencing additional single-read sequencesof cdna fragments.     

Variance estimation for systematic designs in spatial surveys

Summary In spatial surveys for estimating the density of objects in a survey region, systematic designs will generally yield lower variance than random designs. However, estimating the systematic variance is well known to be a difficult problem. Existing methods tend to overestimate the variance, so although the variance is genuinely reduced, it is over‐reported, and the gain from the more efficient design is lost. The current approaches to estimating a systematic variance for spatial surveys are to approximate the systematic design by a random design, or approximate it by a stratified design. Previous work has shown that approximation by a random design can perform very poorly, while approximation by a stratified design is an improvement but can still be severely biased in some situations. We develop a new estimator based on modeling the encounter process over space. The new “striplet” estimator has negligible bias and excellent precision in a wide range of simulation scenarios, including strip‐sampling, distance‐sampling, and quadrat‐sampling surveys, and including populations that are highly trended or have strong aggregation of objects. We apply the new estimator to survey data for the spotted hyena (Crocuta crocuta) in the Serengeti National Park, Tanzania, and find that the reported coefficient of variation for estimated density is 20% using approximation by a random design, 17% using approximation by a stratified design, and 11% using the new striplet estimator. This large reduction in reported variance is verified by simulation.     

Modeling Invasion Dynamics with Spatial Random-Fitness Due to Micro-Environment

Numerous experimental studies have demonstrated that the microenvironment is a key regulator influencing the proliferative and migrative potentials of species. Spatial and temporal disturbances lead to adverse and hazardous microenvironments for cellular systems that is reflected in the phenotypic heterogeneity within the system. In this paper, we study the effect of microenvironment on the invasive capability of species, or mutants, on structured grids (in particular, square lattices) under the influence of site-dependent random proliferation in addition to a migration potential. We discuss both continuous and discrete fitness distributions. Our results suggest that the invasion probability is negatively correlated with the variance of fitness distribution of mutants (for both advantageous and neutral mutants) in the absence of migration of both types of cells. A similar behaviour is observed even in the presence of a random fitness distribution of host cells in the system with neutral fitness rate. In the case of a bimodal distribution, we observe zero invasion probability until the system reaches a (specific) proportion of advantageous phenotypes. Also, we find that the migrative potential amplifies the invasion probability as the variance of fitness of mutants increases in the system, which is the exact opposite in the absence of migration. Our computational framework captures the harsh microenvironmental conditions through quenched random fitness distributions and migration of cells, and our analysis shows that they play an important role in the invasion dynamics of several biological systems such as bacterial micro-habitats, epithelial dysplasia, and metastasis. We believe that our results may lead to more experimental studies, which can in turn provide further insights into the role and impact of heterogeneous environments on invasion dynamics.     

A random effects model for multivariate failure time data from multicenter clinical trials

A random effects model for analyzing multivariate failure time data is proposed. The work is motivated by the need for assessing the mean treatment effect in a multicenter clinical trial study, assuming that the centers are a random sample from an underlying population. An estimating equation for the mean hazard ratio parameter is proposed. The proposed estimator is shown to be consistent and asymptotically normally distributed. A variance estimator, based on large sample theory, is proposed. Simulation results indicate that the proposed estimator performs well in finite samples. The proposed variance estimator effectively corrects the bias of the naive variance estimator, which assumes independence of individuals within a group. The methodology is illustrated with a clinical trial data set from the Studies of Left Ventricular Dysfunction. This shows that the variability of the treatment effect is higher than found by means of simpler models.     

Uniformly minimum variance unbiased estimation of gene diversity

Gene diversity is an important measure of genetic variability in inbred populations. The survival of species in changing environments depends on, among other factors, the genetic variability of the population. In this communication, I have derived the uniformly minimum variance unbiased estimator of gene diversity. The proposed estimator of gene diversity does not assume that the inbreeding coefficient is known. I have also provided the approximate variance of this estimator according to Fisher's method. In addition, I have developed a numerical resampling-based method for obtaining variances and confidence intervals based on the maximum likelihood estimator and the uniformly minimum variance unbiased estimator. Efficiency in estimation of the gene diversity based on these two estimators is discussed. In accordance with the simulation results, I found that the uniformly minimum variance estimator developed in this report is more accurate for estimation of gene diversity than the maximum likelihood estimator.     

Pooling designs for outcomes under a Gaussian random effects model

Due to the rising cost of laboratory assays, it has become increasingly common in epidemiological studies to pool biospecimens. This is particularly true in longitudinal studies, where the cost of performing multiple assays over time can be prohibitive. In this article, we consider the problem of estimating the parameters of a Gaussian random effects model when the repeated outcome is subject to pooling. We consider different pooling designs for the efficient maximum likelihood estimation of variance components, with particular attention to estimating the intraclass correlation coefficient. We evaluate the efficiencies of different pooling design strategies using analytic and simulation study results. We examine the robustness of the designs to skewed distributions and consider unbalanced designs. The design methodology is illustrated with a longitudinal study of premenopausal women focusing on assessing the reproducibility of F2-isoprostane, a biomarker of oxidative stress, over the menstrual cycle.     

Notes in Case-Control Studies with Matched Pairs under Inverse Sampling

In case-control studies with matched pairs, the traditional point estimator of odds ratio (OR) is well-known to be biased with no exact finite variance under binomial sampling. In this paper, we consider use of inverse sampling in which we continue to sample subjects to form matched pairs until we obtain a pre-determined number (>0) of index pairs with the case unexposed but the control exposed. In contrast to use of binomial sampling, we show that the uniformly minimum variance unbiased estimator (UMVUE) of OR does exist under inverse sampling. We further derive an exact confidence interval of OR in closed form. Finally, we develop an exact test and an asymptotic test for testing the null hypothesis H₀: OR = 1, as well as discuss sample size determination on the minimum required number of index pairs for a desired power at α-level.     

On an Unbiased Variance Estimator for the WILCOXON-MANN-WHITNEY-Statistic Based on Ranks

For some applications of the WILCOXON-MANN-WHITNEY-statistic its variance has to be estimated. So e.g. for the test of POTTHOFF (1963) to detect differences in medians of two symmetric distributions as well as for the computation of approximate, confidence bounds for the probability P(X₁ ≥ X₂), cf. GOVINDARAJULU (1968). In the present paper an easy to compute variance estimator is proposed which as only information uses the ranks of the data with the additional property that it is unbiased for the finite variance. Because of its invariance under any monotone transformation of the data its applicability is not confined to quantitative data. The estimator may be applied to ordinal data just as well. Some properties are discussed and a numerical example is given.     

The Petersen–Lincoln Estimator and its Extension to Estimate the Size of a Shared Population

The Petersen–Lincoln estimator has been used to estimate the size of a population in a single mark release experiment. However, the estimator is not valid when the capture sample and recapture sample are not independent. We provide an intuitive interpretation for “independence” between samples based on 2 × 2 categorical data formed by capture/non‐capture in each of the two samples. From the interpretation, we review a general measure of “dependence” and quantify the correlation bias of the Petersen–Lincoln estimator when two types of dependences (local list dependence and heterogeneity of capture probability) exist. An important implication in the census undercount problem is that instead of using a post enumeration sample to assess the undercount of a census, one should conduct a prior enumeration sample to avoid correlation bias. We extend the Petersen–Lincoln method to the case of two populations. This new estimator of the size of the shared population is proposed and its variance is derived. We discuss a special case where the correlation bias of the proposed estimator due to dependence between samples vanishes. The proposed method is applied to a study of the relapse rate of illicit drug use in Taiwan. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

On estimating the heterozygosity and polymorphism information content value

The polymorphism information content (PIC) value is commonly used in genetics as a measure of polymorphism for a marker locus used in linkage analysis. In this communication we have derived the uniformly minimum variance unbiased estimator of PIC along with its exact variance. We have also calculated the exact variance of the maximum likelihood estimator of PIC which is asymptotically an unbiased estimator. In order to find this variance we have derived a recursive formula to calculate the moments of any polynomial in a set of variables that are multinomially distributed.