Some applications of genetics in statistical ecology

Genetic data are in widespread use in ecological research, and an understanding of this type of data and its uses and interpretations will soon be an imperative for ecological statisticians. Here, we provide an introduction to the subject, intended for statisticians who have no previous knowledge of genetics. Although there are numerous types of genetic data, we restrict attention to multilocus genotype data from microsatellite loci. We look at two application areas in wide use: investigating population structure using genetic assignment and related techniques; and using genotype data in capture–recapture studies for estimating population size and demographic parameters. In each case, we outline the conceptual framework and draw attention to both the strengths and weaknesses of existing approaches to analysis and interpretation.     

Modular-transform based clustering

Spectral clustering uses eigenvectors of the Laplacian of the similarity matrix. It is convenient to solve binary clustering problems. When applied to multi-way clustering, either the binary spectral clustering is recursively applied or an embedding to spectral space is done and some other methods, such as K-means clustering, are used to cluster the points. Here we propose and study a K-way clustering algorithm – spectral modular transformation, based on the fact that the graph Laplacian has an equivalent representation, which has a diagonal modular structure. The method first transforms the original similarity matrix into a new one, which is nearly disconnected and reveals a cluster structure clearly, then we apply linearized cluster assignment algorithm to split the clusters. In this way, we can find some samples for each cluster recursively using the divide and conquer method. To get the overall clustering results, we apply the cluster assignment obtained in the previous step as the initialization of multiplicative update method for spectral clustering. Examples show that our method outperforms spectral clustering using other initializations.     

Randomization with non-uniform allocations: fulfillment time distributions and bias properties

This article compares the properties of two balanced randomization schemes with several treatments under non-uniform allocation probabilities. According to the first procedure, the so-called truncated multinomial randomization design, the process employs a given allocation distribution, until a treatment receives its quota of subjects, after which this distribution switches to the conditional distribution for the remaining treatments, and so on. The second scheme, the random allocation rule, selects at random any legitimate assignment of the given number of subjects per treatment. The behavior of these two schemes is shown to be quite different: the truncated multinomial randomization design's assignment probabilities to a treatment turn out to vary over the recruitment period, and its accidental bias can be large, whereas the random allocation rule's this bias is bounded. The limiting distributions of the instants at which a treatment receives the given number of subjects is shown to be that of weighted spacings for normal order statistics with different variances. Formulas for the selection bias of both procedures are also derived.     

Modified d-optimal sequential procedure in allocation problem

When an experimenter wishes to compare t treatments with M experimental units, one of the first problems he faces is how to allocate N experimental units into t treatments. When no pre treat merit information about the experimental units is available, "randomization" is the widely accepted guiding principle to deal with the allocation problem But pre treat merit information usually is available, although it is seldom fully used for allocation purposes. Recently, Harville considered the allocation problem under a covariance model. He suggested a D-optimal sequential procedure that may be used to construct nearly D-optimal allocations. However, Harville's sequential procedure requires constructing a D-optimal initial allocation at the first stages and that may be computationally unfeasible in some real situations, Such construction is not needed for a new sequential.     

The Equivalence of Neyman Optimum Allocation for Sampling and Equal Proportions for Apportioning the U.S. House of Representatives

We present a surprising though obvious result that seems to have been unnoticed until now. In particular, we demonstrate the equivalence of two well-known problems—the optimal allocation of the fixed overall sample size n among L strata under stratified random sampling and the optimal allocation of the H = 435 seats among the 50 states for apportionment of the U.S. House of Representatives following each decennial census. In spite of the strong similarity manifest in the statements of the two problems, they have not been linked and they have well-known but different solutions; one solution is not explicitly exact (Neyman allocation), and the other (equal proportions) is exact. We give explicit exact solutions for both and note that the solutions are equivalent. In fact, we conclude by showing that both problems are special cases of a general problem. The result is significant for stratified random sampling in that it explicitly shows how to minimize sampling error when estimating a total T_Y while keeping the final overall sample size fixed at n; this is usually not the case in practice with Neyman allocation where the resulting final overall sample size might be near n + L after rounding. An example reveals that controlled rounding with Neyman allocation does not always lead to the optimum allocation, that is, an allocation that minimizes variance.     

Statistical considerations in bioequivalence of two area under the concentration–time curves obtained from serial sampling data

In this paper, we study the bioequivalence (BE) inference problem motivated by pharmacokinetic data that were collected using the serial sampling technique. In serial sampling designs, subjects are independently assigned to one of the two drugs; each subject can be sampled only once, and data are collected at K distinct timepoints from multiple subjects. We consider design and hypothesis testing for the parameter of interest: the area under the concentration–time curve (AUC). Decision rules in demonstrating BE were established using an equivalence test for either the ratio or logarithmic difference of two AUCs. The proposed t-test can deal with cases where two AUCs have unequal variances. To control for the type I error rate, the involved degrees-of-freedom were adjusted using Satterthwaite's approximation. A power formula was derived to allow the determination of necessary sample sizes. Simulation results show that, when the two AUCs have unequal variances, the type I error rate is better controlled by the proposed method compared with a method that only handles equal variances. We also propose an unequal subject allocation method that improves the power relative to that of the equal and symmetric allocation. The methods are illustrated using practical examples.     

Optimality of random allocation design for the control of accidental bias in sequential experiments

In comparing two treatments, suppose the suitable subjects arrive sequentially and must be treated at once. Known or unknown to the experimenter there may be nuisance factors systematically affecting the subjects. Accidental bias is a measure of the influence of these factors in the analysis of data. We show in this paper that the random allocation design minimizes the accidental bias among all designs that allocate n, out of 2n, subjects to each treatment and do not prefer either treatment in the assignment. When the final imbalance is allowed to be nonzero, optimal and efficient designs are given. In particular the random allocation design is shown to be very efficient in this broader setup.     

Sample‐size calculations for multi‐group comparison in population pharmacokinetic experiments

This paper describes an approach for calculating sample size for population pharmacokinetic experiments that involve hypothesis testing based on multi‐group comparison detecting the difference in parameters between groups under mixed‐effects modelling. This approach extends what has been described for generalized linear models and nonlinear population pharmacokinetic models that involve only binary covariates to more complex nonlinear population pharmacokinetic models. The structural nonlinear model is linearized around the random effects to obtain the marginal model and the hypothesis testing involving model parameters is based on Wald's test. This approach provides an efficient and fast method for calculating sample size for hypothesis testing in population pharmacokinetic models. The approach can also handle different design problems such as unequal allocation of subjects to groups and unbalanced sampling times between and within groups. The results obtained following application to a one compartment intravenous bolus dose model that involved three different hypotheses under different scenarios showed good agreement between the power obtained from NONMEM simulations and nominal power. Copyright © 2009 John Wiley & Sons, Ltd.     

Optimum treatment allocation for dual-objective clinical trials with binary outcomes

A common problem in randomized controlled clinical trials is the optimal assignment of patients to treatment protocols, The traditional optimal design assumes a single criterion, although in reality, there are usually more than one objective in a clinical trial. In this paper, optimal treatment allocation schemes are found for a dual-objective clinical trial with a binary response. A graphical method for finding the optimal strategy is proposed and illustrative examples are discussed.     

Curve prediction and clustering with mixtures of Gaussian process functional regression models

Shi, Wang, Murray-Smith and Titterington (Biometrics 63:714–723, 2007) proposed a Gaussian process functional regression (GPFR) model to model functional response curves with a set of functional covariates. Two main problems are addressed by their method: modelling nonlinear and nonparametric regression relationship and modelling covariance structure and mean structure simultaneously. The method gives very good results for curve fitting and prediction but side-steps the problem of heterogeneity. In this paper we present a new method for modelling functional data with ‘spatially’ indexed data, i.e., the heterogeneity is dependent on factors such as region and individual patient’s information. For data collected from different sources, we assume that the data corresponding to each curve (or batch) follows a Gaussian process functional regression model as a lower-level model, and introduce an allocation model for the latent indicator variables as a higher-level model. This higher-level model is dependent on the information related to each batch. This method takes advantage of both GPFR and mixture models and therefore improves the accuracy of predictions. The mixture model has also been used for curve clustering, but focusing on the problem of clustering functional relationships between response curve and covariates, i.e. the clustering is based on the surface shape of the functional response against the set of functional covariates. The model is examined on simulated data and real data.     

Modeling Efficiency of Foreign Aid Allocation in Malawi

ABSTRACT

The Open Aid Malawi initiative has collected an unprecedented database that identifies as much location-specific information as possible for each of over 2500 individual foreign aid donations to Malawi since 2003. The efficient use and distribution of such aid is important to donors and to Malawi citizens. However, because of individual donor goals and difficulty in tracking donor coordination it is difficult to determine whether aid allocation is efficient. We compare several Bayesian spatial generalized linear mixed models to relate aid allocation to various economic indicators within seven donation sectors. We find that the spatial gamma regression model best predicts current aid allocation. While we are cautious about making strong claims based on this exploratory study, we provide a methodology by which one could (i) evaluate the efficiency of aid allocation via a study of the locations of current aid allocation as compared to the need at those locations and (ii) come up with a strategy for efficient allocation of resources in conditions where there exists an ideal relationship between aid allocation and economic sectors.     

Pharmacokinetic parameters estimation using adaptive Bayesian P-splines models

In preclinical and clinical experiments, pharmacokinetic (PK) studies are designed to analyse the evolution of drug concentration in plasma over time i.e. the PK profile. Some PK parameters are estimated in order to summarize the complete drug's kinetic profile: area under the curve (AUC), maximal concentration (C(max)), time at which the maximal concentration occurs (t(max)) and half-life time (t(1/2)).Several methods have been proposed to estimate these PK parameters. A first method relies on interpolating between observed concentrations. The interpolation method is often chosen linear. This method is simple and fast. Another method relies on compartmental modelling. In this case, nonlinear methods are used to estimate parameters of a chosen compartmental model. This method provides generally good results. However, if the data are sparse and noisy, two difficulties can arise with this method. The first one is related to the choice of the suitable compartmental model given the small number of data available in preclinical experiment for instance. Second, nonlinear methods can fail to converge. Much work has been done recently to circumvent these problems (J. Pharmacokinet. Pharmacodyn. 2007; 34:229-249, Stat. Comput., to appear, Biometrical J., to appear, ESAIM P&S 2004; 8:115-131).In this paper, we propose a Bayesian nonparametric model based on P-splines. This method provides good PK parameters estimation, whatever be the number of available observations and the level of noise in the data. Simulations show that the proposed method provides better PK parameters estimations than the interpolation method, both in terms of bias and precision. The Bayesian nonparametric method provides also better AUC and t(1/2) estimations than a correctly specified compartmental model, whereas this last method performs better in t(max) and C(max) estimations.We extend the basic model to a hierarchical one that treats the case where we have concentrations from different subjects. We are then able to get individual PK parameter estimations. Finally, with Bayesian methods, we can get easily some uncertainty measures by obtaining credibility sets for each PK parameter.     

Exact confidence regions for species assignment based on DNA markers

Assignment of individuals to correct species or population of origin based on a comparison of allele profiles has in recent years become more accurate due to improvements in DNA marker technology. A method of assessing the error in such assignment problems is présentés. The method is based on the exact hypergeometric distributions of contingency tables conditioned on marginal totals. The result is a confidence region of fixed confidence level. This confidence level is calculable exactly in principle, and estimable very accurately by simulation, without knowledge of the true population allele frequencies. Various properties of these techniques are examined through application to several examples of actual DNA marker data and through simulation studies. Methods which may reduce computation time are discussed and illustrated.     

An adaptive model switching approach for phase I dose‐finding trials

Model‐based phase I dose‐finding designs rely on a single model throughout the study for estimating the maximum tolerated dose (MTD). Thus, one major concern is about the choice of the most suitable model to be used. This is important because the dose allocation process and the MTD estimation depend on whether or not the model is reliable, or whether or not it gives a better fit to toxicity data. The aim of our work was to propose a method that would remove the need for a model choice prior to the trial onset and then allow it sequentially at each patient's inclusion. In this paper, we described model checking approach based on the posterior predictive check and model comparison approach based on the deviance information criterion, in order to identify a more reliable or better model during the course of a trial and to support clinical decision making. Further, we presented two model switching designs for a phase I cancer trial that were based on the aforementioned approaches, and performed a comparison between designs with or without model switching, through a simulation study. The results showed that the proposed designs had the advantage of decreasing certain risks, such as those of poor dose allocation and failure to find the MTD, which could occur if the model is misspecified. Copyright © 2013 John Wiley & Sons, Ltd.     

A NOTE ON OPTIMUM STRATIFICATION FOR EQUAL ALLOCATION WITH RATIO AND REGRESSION METHODS OF ESTIMATION

When the information on a highly positively correlated auxiliary variable x is used to construct stratified regression (or ratio) estimates of the population mean of the study variable y, the paper considers the problem of determining approximately optimum strata boundaries (AOSB) on x when the sample size in each stratum is equal. The form of the conditional variance function V(y/x) is assumed to be known. A numerical investigation into the relative efficiency of equal allocation with respect to the Neyman and proportional allocations has also been made. The relative efficiency of equal allocation with respect to Neyman allocation is found to be nearly equal to one.     

A simple,doubly robust,efficient estimator for survival functions using pseudo observations

Survival functions are often estimated by nonparametric estimators such as the Kaplan‐Meier estimator. For valid estimation, proper adjustment for confounding factors is needed when treatment assignment may depend on confounding factors. Inverse probability weighting is a commonly used approach, especially when there is a large number of potential confounders to adjust for. Direct adjustment may also be used if the relationship between the time‐to‐event and all confounders can be modeled. However, either approach requires a correctly specified model for the relationship between confounders and treatment allocation or between confounders and the time‐to‐event. We propose a pseudo‐observation–based doubly robust estimator, which is valid when either the treatment allocation model or the time‐to‐event model is correctly specified and is generally more efficient than the inverse probability weighting approach. The approach can be easily implemented using standard software. A simulation study was conducted to evaluate this approach under a number of scenarios, and the results are presented and discussed. The results confirm robustness and efficiency of the proposed approach. A real data example is also provided for illustration.     

Water cycle algorithm for solving the reliability-redundancy allocation problem with a choice of redundancy strategies

Abstract

This paper proposes a new mathematical model for the reliability-redundancy allocation problem (RRAP) with a choice of redundancy strategies. To maximize the reliability of a system, this model chooses the best redundancy strategy from among both active and standby ones for each subsystem. For those with a standby strategy, a continuous time Markov chain model is used to calculate the exact reliability values. In order to solve the proposed mixed-integer non-linear programing model, a powerful evolutionary algorithm, called water cycle algorithm (WCA), is developed and implemented on three famous benchmark problems. Finally, the results of different benchmark problems are compared with those previously reported to show the superiority of the proposed model and the efficiency of WCA.     

Adaptive Isotonic Estimation of the Minimum Effective and Peak Doses in the Presence of Covariates

We consider a problem of estimating the minimum effective and peak doses in the presence of covariates. We propose a sequential strategy for subject assignment that includes an adaptive randomization component to balance the allocation to placebo and active doses with respect to covariates. We conclude that either adjusting for covariates in the model or balancing allocation with respect to covariates is required to avoid bias in the target dose estimation. We also compute optimal allocation to estimate the minimum effective and peak doses in discrete dose space using isotonic regression.     

Randomization,balance, and the validity and efficiency of design-adaptive allocation methods

Few topics have stirred as much discussion and controversy as randomization. A reading of the literature suggests that clinical trialists generally feel randomization is necessary for valid inference, while biostatisticians using model-based inference often appear to prefer nearly optimal designs irrespective of any induced randomness. Dissection of the methods of treatment assignment shows that there are five basic approaches; pure randomizers, true randomizers, quasi-randomizers, permutation testers, and conventional modelers. Four of these have coherent design and analysis strategies, even though they are not mutually consistent, but the fifth and most prevalent approach (quasi-randomization) has little to recommend it. Design-adaptive allocation is defined, it is shown to provide valid inference, and a simulation indicates its efficiency advantage. In small studies, or large studies with many important prognostic covariates or analytic subgroups, design-adaptive allocation is an extremely attractive method of treatment assignment.     

A general adaptive allocation design for continuous responses in the presence of covariates

Several adaptive allocation designs are available in the clinical trial literature for allocating the entering patients among two competing treatments, having binary responses and skewing the allocation in favor of the better treatment. No adaptive design is available for continuous responses in the presence of prognostic factors, which is not model based. In the present paper, a general allocation design is introduced which assumes no specific regression model or distribution of responses. Some performance characteristics of the design are studied. Some related inference, following the allocation, is also studied. The proposed procedure is compared with some possible competitors. A real data set is used to illustrate the applicability of the proposed design.