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PubMed2006

Establishing bioequivalence in serial sacrifice designs.

Nonclinical in vivo animal studies have to be completed before starting clinical studies of the pharmacokinetic behavior of a drug in human subjects. The classic complete data design, where each animal is sampled for analysis once per time point, is usually only applicable for large animals using the traditional two-stage approach. The first stage involves estimation of pharmacokinetic parameters for each animal separately and the second stage uses the individual parameter estimates for statistical inference. In the case of rats and mice, where blood sampling is restricted, the batch design or the serial sacrifice design may be applicable. In batch designs samples are taken more than once from each animal, but not at all time points. In serial sacrifice designs only one sample is taken from each animal. In this paper, three methods are presented to construct confidence intervals for the ratio of two AUCs assessed in a serial sacrifice design, which can be used to assess bioequivalence in this parameter. The presented methods are compared in a simulation study.

Animals↗

PubMed2006

A ratio test in active control non-inferiority trials with a time-to-event endpoint.

There are essentially two kinds of non-inferiority hypotheses in an active control trial: fixed margin and ratio hypotheses. In a fixed margin hypothesis, the margin is a prespecified constant and the hypothesis is defined in terms of a single parameter that represents the effect of the active treatment relative to the control. The statistical inference for a fixed margin hypothesis is straightforward. The outstanding issue for a fixed margin non-inferiority hypothesis is how to select the margin, a task that may not be as simple as it appears. The selection of a fixed non-inferiority margin has been discussed in a few articles (Chi et al., 2003; Hung et al., 2003; Ng, 1993). In a ratio hypothesis, the control effect is also considered as an unknown parameter, and the noninferiority hypothesis is then formulated as a ratio in terms of these two parameters, the treatment effect and the control effect. This type of non-inferiority hypothesis has also been called the fraction retention hypothesis because the ratio hypothesis can be interpreted as a retention of certain fraction of the control effect. Rothmann et al. (2003) formulated a ratio non-inferiority hypothesis in terms of log hazards in the time-to-event setting. To circumvent the complexity of having to deal with a ratio test statistic, the ratio hypothesis was linearized to an equivalent hypothesis under the assumption that the control effect is positive. An associated test statistic for this linearized hypothesis was developed. However, there are three important issues that are not addressed by this method. First, the retention fraction being defined in terms of log hazard is difficult to interpret. Second, in order to linearize the ratio hypothesis, Rothmann's method has to assume that the true control effect is positive. Third, the test statistic is not powerful and thus requires a huge sample size, which renders the method impractical. In this paper, a ratio hypothesis is defined directly in terms of the hazard. A natural ratio test statistic can be defined and is shown to have the desired asymptotic normality. The demand on sample size is much reduced. In most commonly encountered situations, the sample size required is less than half of those needed by either the fixed margin approach or Rothmann's method.

Clinical Trials as Topic↗

PubMed2002

Use of Akaike information criteria for model selection and inference. An application to assess prevention of gastrointestinal parasitism and respiratory mortality of Guinean goats in Kolda, Senegal.

A field experiment was carried out in Kolda (southern Senegal) from July 1986 to July 1988. Its goals were to: (1) describe the patterns of mortality of female Guinean goats by age, season and year; (2) assess preventive measures against respiratory diseases and gastrointestinal parasitism in reducing mortality; and (3) estimate the overall impact of these measures on survival to 1 year of age. Preventive measures for respiratory disease included vaccination against peste des petits ruminants (PPR) and pneumonic pasteurellosis (Pasteurella multocida types A and D). Control of gastrointestinal parasites was by deworming does with morantel (7.5mg kg(-1), three times during the rainy season). The effects of vaccines and deworming were tested in a randomised factorial field experiment with villages being the experimental units. A total of 19 villages, 113 goat herds and 1,458 goats were included in the study. Generalised linear models of survival for five cohorts of goats (defined by five different birth seasons) used a binomial assumption for the response distribution and a complementary log-log link. Explanatory variables included age, season, year, vaccination, deworming and their interactions. A complex a priori model was built on the basis of previous epidemiological knowledge; a purposely selected set of simpler models was compared to this full model by the Akaike information criterion (AIC) and derived statistics. Inference on 1-year survival and treatment effects accounted for model-selection uncertainty. It was carried out with a bootstrap procedure and used information from the whole set of selected models. Large variations in mortality by year and season were observed but no regular seasonal pattern was apparent. Mortality probabilities of kids in dewormed groups decreased quickly after birth, but remained elevated up to 9 months of age in the non-dewormed groups. Deworming lowered the risk of mortality. Vaccination alone was not protective (except during an observed outbreak of PPR).

Animals↗

PubMed1990

[Voluntary versus involuntary sample surveys in the microcensus].

The author compares aspects of voluntary and involuntary sample surveys in West Germany. "The German microcensus as a non-voluntary survey draws a random sample from the total population which includes persons that would also respond in a voluntary survey (respondents) and persons that would not respond (non-respondents). The population of a voluntary survey, however, includes only respondents. Hence, statistical inference from a voluntary sample survey is only valid for the total population, if the population of respondents does not differ from the total population. This null hypothesis must be rejected from the comparisons of data from the German microcensus of 1985, 1986 and 1987 and corresponding voluntary test sample surveys. The discrepancies are great in central demographic and socio-economic variables such as region of residence, community size, age, marital status, income and social security." (SUMMARY IN ENG)

Age Factors↗

PubMed2004

Frailty models for arbitrarily censored and truncated data.

In this paper, we propose a frailty model for statistical inference in the case where we are faced with arbitrarily censored and truncated data. Our results extend those of Alioum and Commenges (1996), who developed a method of fitting a proportional hazards model to data of this kind. We discuss the identifiability of the regression coefficients involved in the model which are the parameters of interest, as well as the identifiability of the baseline cumulative hazard function of the model which plays the role of the infinite dimensional nuisance parameter. We illustrate our method with the use of simulated data as well as with a set of real data on transfusion-related AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed2005

A stochastic model to analyze clonal data on multi-type cell populations.

This article presents a stochastic model designed to analyze experimental data on the development of cell clones composed of two (or more) distinct types of cells. The proposed model is an extension of the traditional multi-type Bellman-Harris branching stochastic process allowing for nonidentical time-to-transformation distributions defined for different cell types. A simulated pseudo likelihood method has been developed for the parametric statistical inference from experimental data on cell clones under the proposed model. The method uses simulation-based approximations of the means and the variance-covariance matrices of cell counts. The proposed estimator for the vector of unknown parameters is strongly consistent and asymptotically normal under mild regularity conditions, while its variance-covariance matrix is estimated by the parametric bootstrap. A Monte Carlo Wald test is proposed for the test of hypotheses. Finite sample properties of the estimator have been studied by computer simulations. The model and associated methods of parametric inference have been applied to the analysis of proliferation and differentiation of cultured O-2A progenitor cells that play a key role in the development of the central nervous system. It follows from this analysis that the time to division of the progenitor cell and the time to its differentiation (into an oligodendrocyte) are not identically distributed. This biological finding suggests that a molecular event determining the type of cell transformation is more likely to occur at the start rather than at the end of the mitotic cycle.

Biometry↗

PubMed1997

[Statistical analysis of pharmacological data: problem of multiple comparison].

Problems of multiple comparison were discussed without assuming technical knowledge of statistics. For the first question concerning why to use multiple comparison procedures, theoretical bases of statistical inference and multiple comparison (including type I error rate and familywise error rate) were briefly outlined. For the second question concerning how to properly use multiple comparison procedures, multiple comparison procedures were introduced, and their characteristics were compared. Families of comparisons are different among Dunnett's, Tukey's and Scheffe's tests. Assumptions of dose-response relationship are different among Dunnett's, Williams' tests and linear regression analysis. Duncan's test does not control familywise error rate at a fixed level. For the last question concerning what is remarked for multiple comparison, approaches to several problems such as abnormality and heteroscedasticity were provided. Philosophy and strategy to multiple comparison problems were discussed.

Data Interpretation, Statistical↗

PubMed1987

Methods old and new for analyzing occupational cohort data.

The person-years approach to analyzing mortality data from occupational cohorts was introduced in the midtwentieth century. It cross-classifies all observed deaths and observation times into cells, computes the number of expected deaths for each cell based on referenced mortality rates, and then examines the ratio of total number of observed deaths to total number of expected deaths (the standardized mortality ratio). The maximum likelihood method of statistical inference was developed in the early twentieth century. However, only recently has it been applied to the analysis of occupational cohort data. When so applied, it provides estimates of measures of association between exposures and disease by maximizing the probability of the observed data. This paper shows how recent developments in the use of this tool justify and extend the person-years approach. In particular, problems with the standardized mortality ratio cited in the literature are shown to result from reliance on assumptions that are inappropriate for the data at hand. Methods for testing these assumptions are described. The discussion is illustrated with examples from occupational cohort studies of lung cancer.

Humans↗

PubMed2002

Statistical parametric mapping of hypoxic tissue identified by [(18)F]fluoromisonidazole and positron emission tomography following acute ischemic stroke.

Positron emission tomography (PET) and the ligand [(18)F]fluoromisonidazole ((18)F-FMISO) have been used to image hypoxic tissue in the brain following acute stroke. Existing region of interest (ROI)-based methods of analysis are time consuming and operator-dependent. We describe and validate a method of statistical parametric mapping to identify regions of increased (18)F-FMISO uptake. The (18)F-FMISO PET images were transformed into a standardized coordinate space and intensity normalized. Then t statistic maps were created using a pooled estimate of variance. Statistical inference was based on the theory of Gaussian Random Fields. We examined the homogeneity of variance in normal subjects and the influence of normalization by mean whole brain activity versus mean activity in the contralateral hemisphere. Validity of the distributional assumptions inherent in parametric analysis was tested by comparison with a non-parametric method. The results of parametric analysis were also compared with those obtained with the existing ROI-based method. Variance in uptake at each voxel in normal subjects was homogeneous and not affected by mean voxel activity or distance from the centre of the image. The method of normalization influenced results significantly. Normalization by whole brain mean activity resulted in a smaller volume of tissue being classified as hypoxic compared to normalisation by mean activity in the contralateral hemisphere. The ROI-based method was subject to interobserver variability with a coefficient of variability of 16%. The volumes of hypoxic tissue identified by parametric and nonparametric methods were highly correlated (r = 0.99). These findings suggest that using a pooled variance and contralateral hemisphere normalisation, statistical parametric mapping can be used to objectively identify regions of increased (18)F-FMISO uptake following acute stroke in individual subjects.

Acute Disease↗

PubMed1986

Identifiability, exchangeability, and epidemiological confounding.

Non-identifiability of parameters is a well-recognized problem in classical statistics, and Bayesian statisticians have long recognized the importance of exchangeability assumptions in making statistical inferences. A seemingly unrelated problem in epidemiology is that of confounding: bias in estimation of the effects of an exposure on disease risk, due to inherent differences in risk between exposed and unexposed individuals. Using a simple deterministic model for exposure effects, a logical connection is drawn between the concepts of identifiability, exchangeability, and confounding. This connection allows one to view the problem of confounding as arising from problems of identifiability, and reveals the exchangeability assumptions that are implicit in confounder control methods. It also provides further justification for confounder definitions based on comparability of exposure groups, as opposed to collapsibility-based definitions.

Bayes Theorem↗

PubMed2001

A statistical framework for quantitative trait mapping.

We describe a general statistical framework for the genetic analysis of quantitative trait data in inbred line crosses. Our main result is based on the observation that, by conditioning on the unobserved QTL genotypes, the problem can be split into two statistically independent and manageable parts. The first part involves only the relationship between the QTL and the phenotype. The second part involves only the location of the QTL in the genome. We developed a simple Monte Carlo algorithm to implement Bayesian QTL analysis. This algorithm simulates multiple versions of complete genotype information on a genomewide grid of locations using information in the marker genotype data. Weights are assigned to the simulated genotypes to capture information in the phenotype data. The weighted complete genotypes are used to approximate quantities needed for statistical inference of QTL locations and effect sizes. One advantage of this approach is that only the weights are recomputed as the analyst considers different candidate models. This device allows the analyst to focus on modeling and model comparisons. The proposed framework can accommodate multiple interacting QTL, nonnormal and multivariate phenotypes, covariates, missing genotype data, and genotyping errors in any type of inbred line cross. A software tool implementing this procedure is available. We demonstrate our approach to QTL analysis using data from a mouse backcross population that is segregating multiple interacting QTL associated with salt-induced hypertension.

Algorithms↗

PubMed1997

Cognitive conjunction: a new approach to brain activation experiments.

This paper introduces the concepts and procedures of "cognitive conjunction," a new approach to designing and analyzing cognitive activation experiments. Cognitive conjunction compliments categorical approaches such as cognitive subtraction and requires a specific form of statistical inference that involves the conjunction of several hypotheses. While cognitive subtraction studies are designed such that a pair of tasks differ only by the processing component(s) of interest, cognitive conjunction studies are designed such that two or more distinct task pairs each share a common processing difference. The neural correlates of the process of interest are then associated with the common areas of activation for each task pair. There are two main advantages of cognitive conjunction relative to cognitive subtraction. The first is that it provides a greater latitude for selecting baseline tasks because it is not necessary to control for all but the component of interest. The only constraint on selecting the baseline is that the component of interest is the only process that differs in each task pair. The second advantage is that cognitive conjunction does not depend on "pure insertion"--the assumption that the addition of an extra processing component in the activation task has no effect on the implementation of processes that are also engaged by the baseline task. The differences between the design and the statistical analysis of experiments based on cognitive subtraction, cognitive conjunction, and factorial designs are illustrated with a study of phonological retrieval. Cognitive conjunction analysis indicates that irrespective of whether subjects name words, objects, letters, or colors, there is activation of the left posterior basal temporal lobe, the left frontal operculum, the left thalamus, and the midline cerebellum.

Brain↗

PubMed1988

Analysis of linear and mildly nonlinear relationships using pooled subject data.

The detection of mild nonlinearities and/or state-dependent variability in otherwise linear physiological relationships is generally difficult in the presence of significant measurement errors. Conventional approaches using pooled subject data to increase the degree of freedom for statistical inference are enervated by the resultant introduction of intersubject variability. This paper proposes a new, simple method of pooling multiple subject data for linearity analysis. With the use of a special standardization procedure for the individual response curves, this method allows sensitive detection of occult nonlinearities as well as any state-dependent variability in the underlying relationship. Application of this analytic approach to reported hypercapnic exercise-response data in eight healthy subjects showed that 1) the hypercapnic ventilation-CO2 output relationship is nonlinear with a downward concavity; and 2) the ventilation-tidal volume relationship, which is linear at low tidal volume values, is similar in hypercapnic exercise as in resting hypercapnia or eucapnic exercise.

Data Interpretation, Statistical↗

PubMed2003

Biostatistical methods for the validation of alternative methods for in vitro toxicity testing.

Statistical methods for the validation of toxicological in vitro test assays are developed and applied. Validation is performed either in comparison with in vivo assays or in comparison with other in vitro assays of established validity. Biostatistical methods are presented which are of potential use and benefit for the validation of alternative methods for the risk assessment of chemicals, providing at least an equivalent level of protection through in vitro toxicity testing to that obtained through the use of current in vivo methods. Characteristic indices are developed and determined. Qualitative outcomes are characterised by the rates of false-positive and false-negative predictions, sensitivity and specificity, and predictive values. Quantitative outcomes are characterised by regression coefficients derived from predictive models. The receiver operating characteristics (ROC) technique, applicable when a continuum of cut-off values is considered, is discussed in detail, in relation to its use for statistical modelling and statistical inference. The methods presented are examined for their use for the proof of safety and for toxicity detection and testing. We emphasise that the final validation of toxicity testing is human toxicity, and that the in vivo test itself is only a predictor with an inherent uncertainty. Therefore, the validation of the in vitro test has to account for the vagueness and uncertainty of the "gold standard" in vivo test. We address model selection and model validation, and a four-step scheme is proposed for the conduct of validation studies. Gaps and research needs are formulated to improve the validation of alternative methods for in vitro toxicity testing.

Animal Testing Alternatives↗

PubMed2004

Two-sample scale tests for comparison of metabolic rates for styrene in previously exposed and unexposed groups.

Statistical analysis procedure in two-sample treatment difference, as well as alternative hypothesis, may play a central role in statistical inference, especially in small sample size case. In this paper, simple non-parametric two-sample permutation tests for scale difference based on the Hodges-Lehmann estimator are reformulated, and are applied to a study examining whether previous styrene exposure increases (thus a one-sided alternative hypothesis rather than a two-sided one) the human liver's metabolic ability to convert styrene into styrene oxide, in which a three-compartment physiologically based pharmacokinetic (PBPK) model was used to compare the estimated metabolic constant kappaamong the previously exposed and unexposed groups. Contrary to the previous conclusion, the proposed tests for scale difference identified from a mixed-effects model showed a significant result.

Humans↗

PubMed2005

Dependence of amygdala activation on echo time: results from olfactory fMRI experiments.

Echo time dependence of the BOLD sensitivity is an important topic in fMRI whenever brain regions are considered where the EPI data quality suffers from susceptibility gradients. Here, an fMRI study is presented showing that a reduced echo time EPI sequence significantly enhances the statistical inference in subcortical (limbic) brain regions, with special focus on the amygdala. As a consequence, to facilitate whole-brain fMRI with optimal echo times, a sequence with slice-dependent echo time is demonstrated with a focus on structures suffering from susceptibility changes. The applicability of this method is shown in a second fMRI study aimed at both, cortical, and limbic brain regions. The results are in good agreement with theoretical descriptions of the BOLD sensitivity under the influence of susceptibility gradients.

Adult↗

PubMed2001

Eating disorders and altered eating behaviors in adolescents of normal weight in a Spanish city.

PURPOSE: To study the prevalence of altered eating behaviors or eating disorder-related behaviors among adolescents of normal weight that do not fulfill criteria for anorexia nervosa and bulimia nervosa. METHOD: Cross-sectional study by means of a self-completed questionnaire (School of Nutrition of Granada, Spain) and measurement of weight and height in a population of 491 schoolchildren aged 14-18 years. The statistical inferences and estimation of risk are based on comparison of proportions and means test, and the relative inequality of prevalences. RESULTS: Of 491 adolescents of normal weight, 9% (females 2:1) were following diets; 42% presented "recurrent episodes of binging" with the sensation of loss of self-control; and 41%% avoided specific types of food. Overall, 46.2% presented altered eating behavior. Factors significantly associated with this were the occurrence of periods of food abstinence and the use of purgatives [confidence interval 95% (CI 95%) prevalence ratio (PR) 1.41-2.02]. Compensatory behaviors were present in 33% of the adolescents, predominantly in females (CI 95% PR 1.79-3.07). The prevalences of abnormal eating behaviors were 16.3% for those related to anorexia (A-RB) and 17.1% for those related to bulimia (B-RB), with a clear predominance of females (2:1) and public education. There seems to be a greater aesthetic concern among those with B-RB and more worry about weight among those with A-RB. CONCLUSIONS: A high proportion of adolescents with abnormal eating behaviors and an altered perception of body fat may currently be diagnosed as having atypical eating disorder" (Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision) considering that their body mass index was within normal range.

Adolescent↗

PubMed2002

Variance stabilization applied to microarray data calibration and to the quantification of differential expression.

We introduce a statistical model for microarray gene expression data that comprises data calibration, the quantification of differential expression, and the quantification of measurement error. In particular, we derive a transformation h for intensity measurements, and a difference statistic Deltah whose variance is approximately constant along the whole intensity range. This forms a basis for statistical inference from microarray data, and provides a rational data pre-processing strategy for multivariate analyses. For the transformation h, the parametric form h(x)=arsinh(a+bx) is derived from a model of the variance-versus-mean dependence for microarray intensity data, using the method of variance stabilizing transformations. For large intensities, h coincides with the logarithmic transformation, and Deltah with the log-ratio. The parameters of h together with those of the calibration between experiments are estimated with a robust variant of maximum-likelihood estimation. We demonstrate our approach on data sets from different experimental platforms, including two-colour cDNA arrays and a series of Affymetrix oligonucleotide arrays.

Algorithms↗