A multiple test for comparing two treatments with control: Interval hypotheses approach

In biological experiments, multiple comparison test procedures may lead to a statistically significant difference in means. However, sometimes the difference is not worthy of attention considering the inherent variation in the characteristic. This may be due to the fact that the magnitude of the change in the characteristic under study after receiving the treatment is small, less than the natural biological variation. It then becomes the job of the statistician to design a test that will remove this paradox, such that the statistical significance will coincide with the biological one. The present paper develops a multiple comparison test for comparing two treatments with control by incorporating within-person variation in forming interval hypotheses. Assuming common variance (unknown) for the three groups (control and two treatments) and the width of the interval as intra-individual variation (known), the distribution of the test statistic is obtained as bivariate non-central t . A level f test procedure is designed. A table of critical values for carrying out the test is constructed for f = 0.05. The exact powers are computed for various values of small sample sizes and parameters. The test is powerful for all values of the parameters. The test was used to detect differences in zinc absorption for two cereal diets compared with a control diet. After application of our test, we arrived at the conclusion of homogeneity of diets with the control diet. Dunnett's procedure, when applied to the same data, concluded otherwise. The new test can also be applied to other data situations in biology, medicine and agriculture.     

Approximating probability density functions in hybrid Bayesian networks with mixtures of truncated exponentials

Mixtures of truncated exponentials (MTE) potentials are an alternative to discretization and Monte Carlo methods for solving hybrid Bayesian networks. Any probability density function (PDF) can be approximated by an MTE potential, which can always be marginalized in closed form. This allows propagation to be done exactly using the Shenoy-Shafer architecture for computing marginals, with no restrictions on the construction of a join tree. This paper presents MTE potentials that approximate standard PDF’s and applications of these potentials for solving inference problems in hybrid Bayesian networks. These approximations will extend the types of inference problems that can be modelled with Bayesian networks, as demonstrated using three examples.     

Effects of unmeasured heterogeneity in the linear transformation model for censored data

We investigate the effect of unobserved heterogeneity in the context of the linear transformation model for censored survival data in the clinical trials setting. The unobserved heterogeneity is represented by a frailty term, with unknown distribution, in the linear transformation model. The bias of the estimate under the assumption of no unobserved heterogeneity when it truly is present is obtained. We also derive the asymptotic relative efficiency of the estimate of treatment effect under the incorrect assumption of no unobserved heterogeneity. Additionally we investigate the loss of power for clinical trials that are designed assuming the model without frailty when, in fact, the model with frailty is true. Numerical studies under a proportional odds model show that the loss of efficiency and the loss of power can be substantial when the heterogeneity, as embodied by a frailty, is ignored. An erratum to this article can be found at     

A computationally simple bivariate survival estimator for efficacy and safety

Both treatment efficacy and safety are typically the primary endpoints in Phase II, and even in some Phase III, clinical trials. Efficacy is frequently measured by time to response, death, or some other milestone event and thus is a continuous, possibly censored, outcome. Safety, however, is frequently measured on a discrete scale; in Eastern Cooperative Oncology Group clinical trial E2290, it was measured as the number of weekly rounds of chemotherapy that were tolerable to colorectal cancer patients. For the joint analysis of efficacy and safety, we propose a non-parametric, computationally simple estimator for the bivariate survival function when one time-to-event is continuous, one is discrete, and both are subject to right-censoring. The bivariate censoring times may depend on each other, but they are assumed to be independent of both event times. We derive a closed-form covariance estimator for the survivor function which allows for inference to be based on any of several possible statistics of interest. In addition, we derive its covariance with respect to calendar time of analysis, allowing for its use in sequential studies.     

Detecting homogeneous segments in DNA sequences by using hidden Markov models

In recent years there has been a rapid growth in the amount of DNA being sequenced and in its availability through genetic databases. Statistical techniques which identify structure within these sequences can be of considerable assistance to molecular biologists particularly when they incorporate the discrete nature of changes caused by evolutionary processes. This paper focuses on the detection of homogeneous segments within heterogeneous DNA sequences. In particular, we study an intron from the chimpanzee α-fetoprotein gene; this protein plays an important role in the embryonic development of mammals. We present a Bayesian solution to this segmentation problem using a hidden Markov model implemented by Markov chain Monte Carlo methods. We consider the important practical problem of specifying informative prior knowledge about sequences of this type. Two Gibbs sampling algorithms are contrasted and the sensitivity of the analysis to the prior specification is investigated. Model selection and possible ways to overcome the label switching problem are also addressed. Our analysis of intron 7 identifies three distinct homogeneous segment types, two of which occur in more than one region, and one of which is reversible.     

Testing for No Effect by Cosine Series Methods

The properties of three lack-of-fit tests that are related to non-parametric cosine regression analysis are examined in the context of testing for a constant mean function. Analytic power comparisons of these tests vs a most powerful test are made using intermediate asymptotic relative efficiency. In particular, a data-driven test is produced which is asymptotically as efficient as the most powerful test over a class of alternatives. A small scale simulation experiment is conducted to ascertain the extent that the large sample comparisons are applicable to finite samples.     

A class of weighted dependence measures for bivariate failure time data

This paper considers a class of summary measures of the dependence between a pair of failure time variables over a finite follow-up region. The class consists of measures that are weighted averages of local dependence measures, and includes the cross-ratio-measure and finite region version of Kendall's τ; recently proposed by the authors. Two new special cases are identified that can avoid the need to estimate the bivariate survivor function and that admit explicit variance estimators. Nonparametric estimators of such dependence measures are proposed and are shown to be consistent and asymptotically normal with variances that can be consistently estimated. Properties of selected estimators are evaluated in a simulation study, and the method is illustrated through an analysis of Australian Twin Study data.     

Standard errors for EM estimation

The EM algorithm is a popular method for computing maximum likelihood estimates. One of its drawbacks is that it does not produce standard errors as a by-product. We consider obtaining standard errors by numerical differentiation. Two approaches are considered. The first differentiates the Fisher score vector to yield the Hessian of the log-likelihood. The second differentiates the EM operator and uses an identity that relates its derivative to the Hessian of the log-likelihood. The well-known SEM algorithm uses the second approach. We consider three additional algorithms: one that uses the first approach and two that use the second. We evaluate the complexity and precision of these three and the SEM in algorithm seven examples. The first is a single-parameter example used to give insight. The others are three examples in each of two areas of EM application: Poisson mixture models and the estimation of covariance from incomplete data. The examples show that there are algorithms that are much simpler and more accurate than the SEM algorithm. Hopefully their simplicity will increase the availability of standard error estimates in EM applications. It is shown that, as previously conjectured, a symmetry diagnostic can accurately estimate errors arising from numerical differentiation. Some issues related to the speed of the EM algorithm and algorithms that differentiate the EM operator are identified.     

The fiducial argument and hacking's principle of irrelevance

In a searching analysis of the fiducial argument Hacking (1965) proposed the Principle of Irrelevance as a condition under which the argument is valid. His statement of the Principle was essentially non-mathematical and this paper presents a mathematical development of the Principle. The relationship with likelihood inference is explored and some of the proposed counter-examples to fiducial theory are considered. It is shown that even with the Principle of Irrelevance examples of non-uniqueness of fiducial distributions exist.     

On the distribution of the sum of independent uniform random variables

Motivated by an application in change point analysis, we derive a closed form for the density function of the sum of n independent, non-identically distributed, uniform random variables.