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PubMed1992

Analysis of variance for repeated measures. Data: a generalized estimating equations approach.

Various techniques are available for the analysis of repeated measures data, and the appropriate choice depends on distributional assumptions and study design features. A correct analysis must account for potential dependence between repeated observations on the same subject. Liang and Zeger proposed a more unified approach to the analysis of repeated measures data based on the application of generalized estimating equations. We examine the application of these methods to several types of data in which one estimates the mean response directly for each combination of discrete covariates, and uses an identity link. Computations for fitting this type of model are exceptionally simple. Numerical examples suggest that the proposed approach yields estimation and hypothesis testing results consistent with more specialized methods.

Analysis of Variance↗
PubMed1993

Covariate imbalance and conditional size: dependence on model-based adjustments.

Analysis of covariance (ANCOVA) is frequently recommended to correct for covariate imbalance and to control conditional size of hypothesis tests in randomized designs. Such control, however, depends on the accuracy of the ANCOVA model used to make the adjustments. Examination of residuals together with knowledge of the subject matter are important for obtaining an accurate model. Stratified assignment procedures lessen the dependence of proper control of conditional size on the specific model used in the adjustment procedure.

Age Factors↗
PubMed1995

Small clinical trials: are they all bad?

Statisticians have long argued that randomized controlled trials should be sufficiently large to achieve their purpose, and for common diseases with major public health implications this has brought many benefits. However, there are many instances where it is unrealistic to expect clinicians to provide the information on which sample sizes are calculated and undue emphasis on trial size can be counterproductive. Examples of such trials are given and some general issues discussed, including the unhelpful contribution of hypothesis testing, the need for replication and the role of the statistician.

Humans↗
PubMed1995

A simulation study of estimators for rates of change in longitudinal studies with attrition.

Many longitudinal studies and clinical trials are designed to compare rates of change over time in one or more outcome variables in several groups. Most such studies have incomplete data because some patients drop out before completing the study. The missing data may induce bias and inefficiency in naive estimates of important parameters. This paper uses Monte Carlo methods to compare the bias and efficiency of several two-stage estimators of the effect of treatment on the mean rate of change when the missing data arise from one of four processes. We also study the validity of confidence intervals and the power of hypothesis tests based on these estimates and their standard errors. In general, the weighted least squares estimator does relatively well, as does an analysis of covariance type estimator proposed by Wu et al. The best estimates of variance components are based on complete cases or maximum likelihood.

Analysis of Variance↗
PubMed1995

Inference for smooth curves in longitudinal data with application to an AIDS clinical trial.

We discuss a longitudinal study where data for many subjects are collected at irregular intervals. The study is a randomized trial of HIV infected subjects and the response variable of interest is serum neopterin. The mean of the outcome variable, taken over patients in each treatment group, is assumed to follow a smooth curve. Piecewise cubic polynomials with a moderate number of knots are used to model the curves. A general parametric form is assumed for the covariance structure. Maximum penalized likelihood estimation is used to smooth the over-parameterized curves. Statistical inference for the mean curves, including confidence bands and hypothesis tests, is discussed. Two approaches, one using a Bayesian interpretation of the penalized likelihood and the other based on the asymptotic distribution of the maximum penalized likelihood estimates, are discussed and contrasted. The properties of the confidence bands obtained from these two approaches are evaluated by examining their coverage rates in a simulation study.

Acquired Immunodeficiency Syndrome↗
PubMed2001

A methodology for analysing a repeated measures and survival outcome simultaneously.

A considerable body of literature has arisen over the past 15 years for analysing univariate repeated measures data. It is rare in applied biomedical research, however, for interest to be restricted to a single outcome measure. In previous work, Rochon considered the case of bivariate repeated measures data in which each outcome is a discrete or continuous random variable. A GEE model was prescribed to relate each set of repeated measures to important explanatory variables. The 'seemingly unrelated regression' model was then applied to combine the pair of GEE models into an overall analysis framework. In this paper, we extend this approach to the case in which one endpoint is a repeated measures outcome but the second is a survival endpoint. Estimation and hypothesis testing issues are addressed and the methodology is illustrated with an example.

Humans↗
PubMed2001

A closer look at combining data among a small number of binomial experiments.

In a regulatory environment, the regulators and the regulated may not be able to agree on the use of subjective prior information for a clinical trial. The use of a data-based prior offers a greater possibility for agreement, however, the degree of importance given to the prior data may still be contentious. The use of a hierarchical model to link the prior data and the current trial is shown to provide a relatively objective method for assigning weight to the prior data. Using a series of examples combining two binomial experiments, the effect of a hierarchical model on estimating rates, on the degree to which data is combined and on hypothesis testing is illustrated. In addition, the phenomenon in which combining data reduces the precision is explained. Simpler models based on finite mixtures of beta distributions are shown to work as well as the more computationally intensive, continuous mixtures. Lastly, an example combining three concurrent studies is illustrated. Published in 2001 by John Wiley & Sons, Ltd.

Bayes Theorem↗
PubMed1994

Phagocyte-generated superoxide reduces Fe3+ to displace it from the surface of asbestos.

Injury after exposure to mineral oxide dusts is considered to be mediated by free radical generation. In vitro production of hydroxyl radical by a fibrous silicate increases with the [Fe3+] complexed to the dust surface. The study hypothesis tested was that extracellular fluids and phagocytic cells can decrease concentrations of iron complexed to the surface of a fibrous silicate by employing host chelators and reductants. Such a depletion of surface [Fe3+] would predict decrements in both oxidant generation and the resultant injury after inhalation and instillation of these mineral oxides. Crocidolite (2.0 mg) which was exposed to either 5.0 ml rat plasma or 10.0 ml rat lavage fluid for 1 h had diminished surface [Fe3+]. Similarly, incubations of crocidolite (2.0 mg) with either 10.0 ml rat alveolar macrophages (1.0 x 10(6) cells/ml) or 10.0 ml rat neutrophils (1.0 x 10(7) cells/ml) decreased concentrations of surface iron. In vivo exposures of asbestos contained in chambers allowing or precluding inflammatory cell entry revealed that the influx of phagocytes was associated with greater decreases in surface [Fe3+]. The body chelators transferrin and lactoferrin were unable to extract the metal from fiber surface in vitro. However, superoxide generated by phagocytes did displace the iron from the crocidolite surface. We conclude that extracellular fluids and phagocytic cells have a capacity to diminish [Fe3+] complexed to the surface of asbestos and therefore decrease the potential for oxidative stress and injury to a living system after exposure to these dusts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Genetic correlates of social behaviour in wild chimpanzees: evidence from mitochondrial DNA

This study explored some aspects of chimpanzee social behaviour using mitochondrial DNA sequence data as an index of matrilineal relatedness. The hypothesis tested was that matrilineal relatedness predicts social affiliative preference in wild chimpanzees. Several behavioural measures of individual social preference were examined for chimpanzees from Kanyawara community in Uganda's Kibale Forest. None of the four pairs of strongly affiliative males in this community could have been maternal brothers, since no pair shared the same mitochondrial DNA sequence. Fourteen chimpanzee communities outside Kibale, for which no direct behavioural data were available, were also studied by using communal nesting as a rough index of affiliative preference. Again, chimpanzees that nested together did not tend to be matrilineally related. The results suggest that kin selection is weaker than previously thought as a force promoting intra-community affiliation in chimpanzees.1997The Association for the Study of Animal Behaviour

Journal Article↗
PubMed1995

Reading direction and attention: effects on lateralized ignoring.

The effects of the scan for the first element in reading (leftmost in English, rightmost in Hebrew) on the ability of subjects to ignore irrelevant stimuli in one visual field more than in the other were investigated. The hypothesis tested was that English readers would have a harder time ignoring irrelevant stimuli in the left visual field than in the right visual field, with the opposite pattern predicted for readers of Hebrew. The paradigm employed by Banich (Banich & Belger, 1990) was used with two letter matching tasks. The results showed that when an irrelevant letter was present, English readers responded more slowly in the right than in the left visual field, and Hebrew readers showed the opposite pattern (Experiment 1). This interaction did not occur when the irrelevant letter was deleted (Experiment 2). These findings are discussed in terms of their relation to eye movements and covert attention and to the use of bilateral displays in neuropsychological experiments.

Attention↗
PubMed1999

Agrammatic production of subject-verb agreement: the effect of conceptual number.

Three experiments tested the hypothesis that the deficit underlying agrammatic sentence production difficulties can be characterized as a limitation of computational resources and that these resources are not restricted to syntactic processing. This hypothesis was tested by eliciting subject-verb agreement errors in a sentence fragment completion paradigm. Sentence fragments were complex noun phrases, containing a subject (head) noun and a modifying prepositional phrase, containing a "local" noun. We varied the number of "tokens" a singular head noun referred to. Therefore, in one condition, grammatical and conceptual number of the head noun mismatched, whereas these numbers were the same in another condition. In Experiments 1 and 2, we observed an effect of this variable (i.e., more agreement errors when conceptual number was plural and grammatical number singular) in normal controls. Broca's aphasics, on the other hand, showed no effect. Experiment 3 consisted of a sentence/picture matching test. This test showed that the lack of effect with Broca's aphasics cannot be attributed to a comprehension deficit. We argue that these results are incompatible with the notion of a limitation in resources specific for syntactic processing. Instead, we interpret this as the result of a trade-off: Broca's aphasics lack computational resources to take into account both grammatical and conceptual information in morphosyntactic processing and rely on grammatical information only.

Adult↗
PubMed1994

Concerning the analysis of 2 x 2 tables.

Recent papers (R. M. Engeman and G. D. Swanson, 1991, Comput. Biomed. Res. 24, 509; M. R. Massai and P. Barbini, 1993, Comput. Biomed Res. 26, 98) have expressed concern regarding differences in results among statistical methods of hypothesis testing for 2 x 2 contingency tables. These papers did not present current statistical thought on this topic, and they did not discuss measures of effect for such analyses. In this paper statistical literature on the 2 x 2 contingency table is presented and philosophical issues underlying the methods discussed. Measures of effect appropriate for several data origins or designs which result in 2 x 2 arrays are also presented. The paper presents an empirical adjustment to the Fisher's exact test known as the mid-P approach. The information should help provide the user of statistics a better understanding of the analysis of 2 x 2 tables. An example using data from Engeman and Swanson (1991) is provided, and some recommendations for the analysis of 2 x 2 tables are given.

Aged↗
PubMed1997

Detecting chaos in HRV signals in human cardiac transplant recipients.

A statistical approach to chaos identification in time series is presented. The method is applied to numerical data generated by chaotic systems and to heart rate variability (HRV) signals of normal subjects and heart transplant recipients. This method compares the short-term predictability for a given time series to an ensemble of random data which has the same Fourier spectrum as the original time series. The short-term prediction error is computed as a discriminating statistic for performing statistical hypothesis testing. The results suggest that HRV signals of the transplant recipients recorded 3 months after the transplantations show the same signature of chaos as that of the HRV signals for normal subjects.

Algorithms↗
PubMed1999

A novel algorithm for the heart rate variability analysis of short-term recordings: polar representation of respiratory sinus arrhythmia.

A new method for the analysis of heart rate variability in short-term recordings is presented which consists of an analysis of the respiratory sinus arrhythmia in the time domain by means of a polar representation. Its main advantage is that it is applicable in experiments in which the respiration of the subject is not controlled. The algorithm is applied to data recorded on two astronauts during the Euromir-95 space mission. Statistical hypothesis tests demonstrate that the presence of a mouthpiece induces an increase of the respiratory sinus arrhythmia amplitude.

Algorithms↗
PubMed2000

Chemokine production by rat myocytes exposed to interferon-gamma.

Messenger RNA that encodes for monocyte chemotactic protein-1 (MCP-1), as well as its protein product, was observed to be constitutively expressed at low levels in a monoclonal Lewis rat skeletal muscle cell line (LE1). Immunohistochemical analyses of sections of skeletal muscle yielded similar results. Since interferon-gamma (IFN-gamma) has been reported to have a likely role in determining the severity of symptoms in the neuromuscular autoimmune disease experimental myasthenia gravis (EAMG), the hypothesis tested and proven true in these studies was that IFN-gamma would up-regulate the production of MCP-1 in LE1 cells. It was also observed that muscle-derived MCP-1 could be up-regulated in vivo in rats receiving a monoclonal anti-acetylcholine receptor antibody (mAb35), a potent inducer of symptoms of EAMG. Therefore, it is concluded that muscle may contribute to disease progression by producing factors that influence activities of the immune system.

Animals↗
PubMed1994

Globin gene server: a prototype E-mail database server featuring extensive multiple alignments and data compilation for electronic genetic analysis.

The sequence of virtually the entire cluster of beta-like globin genes has been determined from several mammals, and many regulatory regions have been analyzed by mutagenesis, functional assays, and nuclear protein binding studies. This very large amount of sequence and functional data needs to be compiled in a readily accessible and usable manner to optimize data analysis, hypothesis testing, and model building. We report a Globin Gene Server that will provide this service in a constantly updated manner when fully implemented. The Server has two principal functions. The first (currently available) provides an annotated multiple alignment of the DNA sequences throughout the gene cluster from representatives of all species analyzed. The second compiles data on functional and protein binding assays throughout the gene cluster. A prototype of this compilation using the aligned 5' flanking region of beta-globin genes from five species shows examples of (1) well-conserved regions that have demonstrated functions, including cases in which the functional data are in apparent conflict, (2) proposed functional regions that are not well conserved, and (3) conserved regions with no currently assigned function. Such an electronic genetic analysis leads to many readily testable hypotheses that were not immediately apparent without the multiple alignment and compilation. The Server is accessible via E-mail on computer networks, and printed results can be obtained by request to the authors. This prototype will be a helpful guide for developing similar tools for many genomic loci.

Animals↗
PubMed1998

Sex ratio and the infection process in entomopathogenic nematodes: are males the colonizing Sex?

In laboratory assays, male infective juveniles of some species of entomopathogenic nematodes in the genus Steinernema differ from females in their tendency to disperse and in their responses to the volatile cues emitted by parasitized and nonparasitized insects. These differences suggest that male infective juveniles might locate and establish in insect hosts before females, and that infection by males might render hosts suitable for nematode development and more attractive to females: "the male colonization hypothesis." We tested this hypothesis in laboratory experiments in which larvae of the greater wax moth, Galleria mellonella (L.), were exposed to infective juveniles of S. glaseri (Steiner) (NC strain) in sand columns for various periods of time. The hosts were dissected to determine the sex ratio of the adult nematodes that became established. We found that infective juveniles entered hosts over periods of up to at least 14 h, and that sex ratios varied among experiments. However, there were no temporal differences in colonization by males and females during the infection process: the proportion of males in host cadavers was not related to exposure time or to the total number of nematodes in host cadavers. This result is inconsistent with the male colonization hypothesis. We conclude that differential colonization of hosts over time by males and females either does not occur in S. glaseri, or occurs only rarely or under conditions differing from ours, or occurs to such a small extent that it is difficult to detect. In S. glaseri, male infective juveniles tend to emerge from host cadavers before females. This might give males an advantage over females in locating new hosts following a natural emergence. Nonetheless, to date, males have not been shown to colonize hosts before females in any steinernematid species. Copyright 1998 Academic Press.

Journal Article↗
PubMed1997

[3H]dofetilide binding to cardiac myocytes: modulation by extracellular potassium.

UNLABELLED: The radioligand [3H]dofetilide binds specifically to the delayed rectifier potassium channel and provides a biochemical approach to study interactions of Class III drugs with this channel. However, previous studies have examined the binding of [3H]dofetilide to cardiac myocytes only at extracellular potassium of 135 mM. Because previous electrophysiological studies have shown that hyperkalemia could alter the pharmacological responses to I(Kr) channel blockers, the hypothesis tested in this study was that changing ionic conditions would alter characteristics of [3H]dofetilide binding. RESULTS: under physiological conditions (Na+ 135 mM, K+ 5 mM), [3H]dofetilide bound to two sites on guinea-pig ventricular myocytes (a high-affinity site, K(d) 26+/-8 nM, B(max) 81+/-12 fmol/10(6) cells: and a low-affinity site, K(d) 1.6+/-0.8 microM, B(max) 1003+/-173 fmol/10(6) cells, n=11). Binding properties were not altered by changes in osmolarity or extracellular sodium. However, when extracellular K+ was increased to 20 mM, a single binding site was observed with an affinity K(d) of 120+12 nM and a B(max) of 303+/-57 fmol/10(6) cells (P<0.05; n=6). To establish whether this effect was mediated at the high-affinity site we assessed the effects of elevated extracellular potassium on a biological model, neonatal mouse myocytes, that expressed solely the high-affinity binding sites. The K(d) values for binding to fetal mouse cardiac myocytes at an extracellular K+ of 5 mM and 20 mM were also significantly different, 29+/-10 and 230+/-46 nM, respectively. In conclusion, [3H]dofetilide binding to its high-affinity site is modulated by extracellular potassium.

Animals↗