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A case of ganciclovir-resistant cytomegalovirus (CMV) retinitis in a patient with AIDS: longitudinal molecular analysis of the CMV viral load and viral mutations in blood compartments.

OBJECTIVE: To study the temporal relationships between cytomegalovirus (CMV) viral load and specific UL97 mutations in polymorphonuclear leukocytes (PMNL) and plasma samples from a patient with AIDS who developed ganciclovir-resistant CMV retinitis. METHODS: Sequential PMNL and plasma samples were analysed for determination of the CMV viral load using non-molecular methods and a quantitative polymerase chain reaction (PCR) assay. Screening of the same samples for the most common mutations conferring ganciclovir resistance was performed using nested PCR and restriction enzyme analysis. RESULTS: At the time of progression of CMV retinitis (after 6 months of ganciclovir), a rapid increase in the CMV DNA load was found in both PMNL and plasma samples. This increase paralleled the emergence of a specific mutation (V594) in the same samples and recovery of ganciclovir-resistant blood isolates. In this patient, however, the only tests that substantially predicted the progression of CMV disease were the quantitative PCR assay using PMNL and to a lesser extent the pp65 antigenemia assay. CONCLUSIONS: Quantitative evaluation of the CMV viral load in PMNL using sensitive assays such as PCR appears to be a promising approach for monitoring antiviral therapy in subjects with AIDS. In addition, common mutations conferring ganciclovir resistance can be detected directly in PMNL and plasma samples.

AIDS-Related Opportunistic Infections↗

Longitudinal population analysis of dual infection with recombination in two strains of HIV type 1 subtype B in an individual from a Phase 3 HIV vaccine efficacy trial.

This study documents a case of coinfection (simultaneous infection of an individual with two or more strains) of two HIV-1 subtype B strains in an individual from a Phase 3 HIV-1 vaccine efficacy trial, conducted in North American and the Netherlands. We examined 86 full-length gp120 (env) gene sequences from this individual collected from nine different time points over a 20-month period. We estimated evolutionary relationships using maximum likelihood and Bayesian methods and inferred recombination breakpoints and recombinant sequences using phylogenetic and substitutional methods. These analyses identified two strongly supported monophyletic clades (clades A and B) of 14 and 69 sequences each and a small paraphyletic recombinant clade of three sequences. We then studied the genetic characteristics of these lineages by comparing estimates of genetic diversity generated by mutation and recombination and adaptive selection within a coalescent and maximum likelihood framework. Our results suggest significant differences on the evolutionary dynamics of these strains. We then discuss the implications of these results for vaccine development.

AIDS Vaccines↗

Longitudinal correlation analysis of standing height and intelligence.

Intercorrelations of 10 successive years of measurement of height and intelligence are presented for separate samples of girls and boys. These correlations are based on data originally gathered and published by Dearborn, Rothney, and Shuttleworth as the Harvard Growth Study. Sample size varies from correlation to correlation, but most of those for girls are based on samples of 500-700 and those for boys on samples of 400-500. The intercorrelations of each of the 2 variables over 10 occasions do not differ appreciably by sex, but there are significant differences between the sexes in the cross-correlations. For the sample of girls there is clear evidence that individual differences in height at 8 and 9 anticipate later individual differences in intelligence. Correlations of early height with intelligence at 11 and 12 are especially high (.40). There is little evidence for similar anticipation of intelligence by height for boys. Correlates for both height and intelligence are found in socioeconomic status, ethnicity, and age of first menstruation for girls. Only the last of these contributes to the explanation of the changes in the cross-correlations with age. Analyses of sitting-height correlations with intelligence indicate that length of the long bones of the legs is also related to the observed pattern of correlations.

Adolescent↗

Longitudinal genetic analysis of problem behaviors in biologically related and unrelated adoptees.

The genetic and environmental influences on problem behaviors at two assessment points, three years apart, and their stability were studied in a sample of international adoptees, initially aged 10 to 15 years. Parents of 111 pairs of adopted biological siblings, 221 pairs of adopted nonbiological siblings and 1484 adopted singletons completed the Child Behavior Checklist (75 pairs, 154 pairs and 1080 singletons respectively at second assessment). At first assessment, genetic factors accounted for more than 50% of the variance in the Externalizing, Aggressive Behavior, Attention Problems and Social Problems scales. Shared environmental influences explained 40% of the variance in the Total Problem scale and less for all other scales. Nonshared environmental influences were most important for the Internalizing scale and its subscales, and for the Thought Problems and Delinquent Behavior scales. At the second assessment, genetic factors explained most of the variance in the Total Problem, Externalizing and Aggressive Behavior scales, while nonshared environmental influences explained most of the variance in all other scales. Shared environmental influences explained 33% of the variance in the Internalizing scale and less for the other scales. The stability of the Externalizing scale over time was caused mostly by genetic factors, while nonshared environmental factors mostly caused the stability of the Internalizing scale.

Adolescent↗

Longitudinal growth analysis of horses following limited and ad libitum feeding.

Eighteen colts were assigned to one of two groups: limit or ad libitum feeding. Three periods were evaluated: 1) six to 12 months, 2) 12 to 18 months and 3) 18 to 24 months of age. At 24 months of age, ad libitum fed horses weighed 13 per cent (51 kg) more and were 3.6 per cent (5.2 cm) taller than those fed limited amounts. Total, fore and hind body mass increased quadratically irrespective of dietary treatment. Fore body mass comprised 57 per cent of total body mass for both groups and this did not change with age or dietary treatment. Heart girth was directly related (R2 = 0.96) to total body mass. Average daily gains in total body mass of ad libitum fed horses were 13 and 71 per cent more rapid (P less than 0.05) than for limit fed horses in Periods 1 and 3, respectively. Ad libitum fed horses gained hind body mass 25 per cent more rapidly (P less than 0.05) than limit fed horses only in Period 1. Growth curves of wither and croup heights were quadratic in form. Ad libitum fed horses gained 12 and 13 per cent more rapidly at the wither than limit fed horses in Period 1 and overall, respectively. Ad libitum fed horses grew 33 per cent more rapidly at the croup than limit fed horses but only in Period 2. From six to 12 months of age, the wither and croup grew two-fold and four-fold more rapidly than between 12 to 18 months and between 18 to 24 months of age, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

Longitudinal Gompertzian analysis of ALS mortality in England and Wales, 1963-1989: estimates of susceptibility in the general population.

Mortality statistics in amyotrophic lateral sclerosis (ALS), which is more commonly and generally termed motoneurone disease (MND) in the United Kingdom, have been shown to reflect the incidence of previously diagnosed cases of the disease in a more complete way than in other conditions [1,2]. An analysis of changing patterns of mortality may therefore be a particularly appropriate way of tracing the underlying trends in the disease and is in principle a useful way of investigating the relationship between environmental and genetically controlled factors in the genesis of the condition. The majority of analyses so far have concentrated on the crude rise in reported mortality rates evident in recent decades in a number of countries [2-5], on the uneven geographical distribution [6,7] and on the complex range of plausible causes for these reported rises. Debates have centred on whether the increases represent 'real' or 'artifactual' changes, with no apparent resolution of the issue [8,3]. Recently Riggs [9] proposed a novel way of analysing this issue by using a Gompertzian model and provided evidence of the existence of an inherently susceptible subset of the US population. Riggs indicated that while the rise in ALS mortality is real, it is for the most part the result of an increase in the size of this inherently susceptible sub-population due to greater longevity. In order to examine the wider applicability of a Gompertzian model to ALS the technique has been replicated with the mortality rates for England and Wales for the 27-year period from 1963 to 1989. The technique has been developed and extended to produce an estimate of the size of the inherently susceptible sub-population (both male and female) over the entire period.

Adolescent↗

A comparison of six different ways of expressing the bronchodilating response in asthma and COPD; reproducibility and dependence of prebronchodilator FEV1.

Various indices are used to express the bronchodilating response. It is unclear, however, which index is most informative. The aim of this study was to compare six expressions of the bronchodilating response and to examine: 1) the independence of the prebronchodilator forced expiratory volume in one second (FEV1); and 2) the reproducibility of the bronchodilating response. Bronchodilating responses (increases in FEV1 60 min after salbutamol 400 micrograms and ipratropium bromide 80 micrograms) on six test occasions, during two years, of 183 patients (72 asthma, 111 chronic obstructive pulmonary disease (COPD)) from a large bronchodilator intervention study were used. The dependence of the prebronchodilator FEV1 was investigated both between patients (cross-sectional analysis) and within patients (longitudinal analysis) by means of linear regression analysis. The reproducibility of the bronchodilating response was calculated by means of the coefficients of variation (CVs) of the six bronchodilating responses during two years. The CVs of the six expression indices were compared by analysis of variance (ANOVA). No index was independent of the prebronchodilator FEV1. However, some indices were significantly more dependent on the prebronchodilator lung function and, therefore, less reproducible than others. The "% initial" index (change as a percentage of the prebronchodilator value) was the most dependent on the prebronchodilator lung function and had the worst reproducibility (CV ranged from 50-61%). The "% possible" (change as a percentage of the predicted minus prebronchodilator value) and "% achievable" (change as a percentage of the maximal postbronchodilator minus prebronchodilator value) indices were the least dependent on the prebronchodilator value and had the highest reproducibility (CV ranging from 34-53%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Gibbs sampler for the logistic model in the analysis of longitudinal binary data.

Logistic mixed-effects models constitute a natural framework to study longitudinal binary response variables when the question addressed with the data is related to covariate effects within persons. However, the computations of the likelihoods are generally tedious and require the resolution of integrals which have no analytical solution. In this paper, we study a logistic mixed-effects model in a Bayesian framework and use the Gibbs sampler to overcome the current computational limitations. From a study of side-effects occurring during plasma exchanges, we explore the issues of bayesian formulation, model parametrization, choice of the prior distributions, diagnosing convergence, comparison between models and model adequacy. Finally, we show that a Bayesian random-effects model is useful to facilitate prediction.

Bayes Theorem↗

A robust mixed linear model analysis for longitudinal data.

This paper describes robust procedures for estimating parameters of a mixed effects linear model as applied to longitudinal data. In addition to fixed regression parameters, the model incorporates random subject effects to accommodate between-subjects variability and autocorrelation for within-subject variability. Robust empirical Bayesian estimation of subject effects is briefly discussed. As an illustration, the procedures are applied to data from a multiple sclerosis clinical trial.

Adjuvants, Immunologic↗

Analysis of longitudinal data from twins.

Longitudinal data from twin pairs may be used to determine how the genetic effects influencing a quantitative trait change with age. Here a model for mixed longitudinal data of Huggins and Loesch [1998] on unrelated individuals is extended to twin studies. The model is fitted using robust statistical methods and a bootstrap procedure is proposed to estimate the percentiles. The method is applied to longitudinal twin data on body mass index in male and female twin pairs aged 5-18 years.

Adolescent↗

Sensitivity analysis of longitudinal binary quality of life data with drop-out: an example using the EORTC QLQ-C30.

Analysing quality of life data (QOL) may be complicated for several reasons. Quality of life data not only involves repeated measures but is also usually collected on ordered categorical responses. In addition, it is evident that not all patients provide the same number of assessments, due to attrition caused by death or other medical reasons. In the recent statistical literature, increasing attention is given to methods which can handle non-continuous outcomes in the presence of missing data. The aim of this paper is to investigate the effect on statistical conclusions of applying different modelling techniques to QOL data generated from an EORTC phase III trial. Treatment effects and treatment differences are of major concern. First, a random-effects model is fitted, relating a binary longitudinal response (derived from the physical functioning scale of the QLQ-C30) to several covariates. In a second approach, marginal models are fitted, retaining the response variable and the mean structure used before. The fitted marginal models only differ with respect to the considered estimation procedure: generalized estimating equations (GEE); weighted generalized estimating equations (WGEE), and maximum likelihood (ML).

Antibiotics, Antineoplastic↗

An illness-death stochastic model in the analysis of longitudinal dementia data.

A significant source of missing data in longitudinal epidemiological studies on elderly individuals is death. Subjects in large scale community-based longitudinal dementia studies are usually evaluated for disease status in study waves, not under continuous surveillance as in traditional cohort studies. Therefore, for the deceased subjects, disease status prior to death cannot be ascertained. Statistical methods assuming deceased subjects to be missing at random may not be realistic in dementia studies and may lead to biased results. We propose a stochastic model approach to simultaneously estimate disease incidence and mortality rates. We set up a Markov chain model consisting of three states, non-diseased, diseased and dead, and estimate the transition hazard parameters using the maximum likelihood approach. Simulation results are presented indicating adequate performance of the proposed approach.

Aged↗

An appraisal of methods for the analysis of longitudinal categorical data with MAR drop-outs.

A number of methods for analysing longitudinal ordinal categorical data with missing-at-random drop-outs are considered. Two are maximum-likelihood methods (MAXLIK) which employ marginal global odds ratios to model associations. The remainder use weighted or unweighted generalized estimating equations (GEE). Two of the GEE use Cholesky-decomposed standardized residuals to model the association structure, while another three extend methods developed for longitudinal binary data in which the association structures are modelled using either Gaussian estimation, multivariate normal estimating equations or conditional residuals. Simulated data sets were used to discover differences among the methods in terms of biases, variances and convergence rates when the association structure is misspecified. The methods were also applied to a real medical data set. Two of the GEE methods, referred to as Cond and ML-norm in this paper and by their originators, were found to have relatively good convergence rates and mean squared errors for all sample sizes (80, 120, 300) considered, and one more, referred to as MGEE in this paper and by its originators, worked fairly well for all but the smallest sample size, 80.

Biometry↗

An autoregressive linear mixed effects model for the analysis of longitudinal data which show profiles approaching asymptotes.

In longitudinal data, a continuous response sometimes shows a profile approaching an asymptote. For such data, we propose a new class of models, autoregressive linear mixed effects models in which the current response is regressed on the previous response, fixed effects, and random effects. Asymptotes can shift depending on treatment groups, individuals, and so on, and can be modelled by fixed and random effects. We also propose error structures that are useful in practice. The estimation methods of linear mixed effects models can be used as long as there is no intermittent missing.

Azathioprine↗

Unobserved heterogeneity and the analysis of longitudinal spatial choice data.

"This paper tackles the problem of handling uncontrolled heterogeneity due to unobserved influences on the decision process of spatial choice. It concentrates upon a discrete-time/'random-effects' approach to the problem of unobserved heterogeneity and documents parametric and non-parametric methods of specifying and estimating models which can cope with unobserved heterogeneity." The model is applied to data from Wales. (SUMMARY IN FRE)

Behavior↗

Analysis of longitudinal health-related quality of life data with terminal events.

Longitudinal health-related quality of life data arise naturally from studies of progressive and neurodegenerative diseases. In such studies, patients' mental and physical conditions are measured over their follow-up periods and the resulting data are often complicated by subject-specific measurement times and possible terminal events associated with outcome variables. Motivated by the "Predictor's Cohort" study on patients with advanced Alzheimer disease, we propose in this paper a semiparametric modeling approach to longitudinal health-related quality of life data. It builds upon and extends some recent developments for longitudinal data with irregular observation times. The new approach handles possibly dependent terminal events. It allows one to examine time-dependent covariate effects on the evolution of outcome variable and to assess nonparametrically change of outcome measurement that is due to factors not incorporated in the covariates. The usual large-sample properties for parameter estimation are established. In particular, it is shown that relevant parameter estimators are asymptotically normal and the asymptotic variances can be estimated consistently by the simple plug-in method. A general procedure for testing a specific parametric form in the nonparametric component is also developed. Simulation studies show that the proposed approach performs well for practical settings. The method is applied to the motivating example.

Health Status↗