PubMed Health⌕ Search

Biomedical subjects

R J Carroll

Publications and source records attributed to R J Carroll.

At least 19 recordsLinked to original sources
PubMed2005

Simple fitting of subject-specific curves for longitudinal data.

We present a simple semiparametric model for fitting subject-specific curves for longitudinal data. Individual curves are modelled as penalized splines with random coefficients. This model has a mixed model representation, and it is easily implemented in standard statistical software. We conduct an analysis of the long-term effect of radiation therapy on the height of children suffering from acute lymphoblastic leukaemia using penalized splines in the framework of semiparametric mixed effects models. The analysis revealed significant differences between therapies and showed that the growth rate of girls in the study cannot be fully explained by the group-average curve and that individual curves are necessary to reflect the individual response to treatment. We also show how to implement these models in S-PLUS and R in the appendix.

Biometry↗
PubMed2003

Genomic profiles and predictive biological networks in oxidant-induced atherogenesis.

Atherogenic stimuli trigger complex responses in vascular smooth muscle cells (VSMCs) that culminate in activation/repression of overlapping signal transduction cascades involving oxidative stress. In the case of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon present in tobacco smoke, the atherogenic response involves interference with redox homeostasis by oxidative intermediates of BaP metabolism. The present studies were conducted to define genomic profiles and predictive gene biological networks associated with the atherogenic response of murine (aortic) VSMCs to BaP. A combined oxidant-antioxidant treatment regimen was used to identify redox-sensitive targets during the early course of the atherogenic response. Gene expression profiles were defined using cDNA microarrays coupled to analysis of variance and several clustering methodologies. A predictor algorithm was then applied to gain insight into critical gene-gene interactions during atherogenesis. Supervised and nonsupervised analyses identified clones highly regulated by BaP, unaffected by antioxidant, and neutralized by combined chemical treatments. Lymphocyte antigen-6 complex, histocompatibility class I component factors, secreted phosphoprotein, and several interferon-inducible proteins were identified as novel redox-regulated targets of BaP. Predictor analysis confirmed these relationships and identified immune-related genes as critical molecular targets of BaP. Redox-dependent patterns of gene deregulation indicate that oxidative stress plays a prominent role during the early stages of BaP-induced atherogenesis.

Algorithms↗
PubMed2002

Dietary n-3 PUFA affect TcR-mediated activation of purified murine T cells and accessory cell function in co-cultures.

Diets enriched in n-3 polyunsaturated fatty acids (PUFA) suppress several functions of murine splenic T cells by acting directly on the T cells and/or indirectly on accessory cells. In this study, the relative contribution of highly purified populations of the two cell types to the dietary suppression of T cell function was examined. Mice were fed diets containing different levels of n-3 PUFA; safflower oil (SAF; control containing no n-3 PUFA), fish oil (FO) at 2% and 4%, or 1% purified docosahexaenoic acid (DHA) for 2 weeks. Purified (>90%) T cells were obtained from the spleen, and accessory cells (>95% adherent, esterase-positive) were obtained by peritoneal lavage. Purified T cells or accessory cells from each diet group were co-cultured with the alternative cell type from every other diet group, yielding a total of 16 different co-culture combinations. The T cells were stimulated with either concanavalin A (ConA) or antibodies to the T cell receptor (TcR)/CD3 complex and the costimulatory molecule CD28 (alphaCD3/alphaCD28), and proliferation was measured after four days. Suppression of T cell proliferation in the co-cultures was dependent upon the dose of dietary n-3 PUFA fed to mice from which the T cells were derived, irrespective of the dietary treatment of accessory cell donors. The greatest dietary effect was seen in mice consuming the DHA diet (P = 0.034 in the anova; P=0.0053 in the Trend Test), and was observed with direct stimulation of the T cell receptor and CD28 costimulatory ligand, but not with ConA. A significant dietary effect was also contributed accessory cells (P = 0.033 in the Trend Test). We conclude that dietary n-3 PUFA affect TcR-mediated by T cell activation by both direct and indirect (accessory cell) mechanisms.

Animals↗
PubMed2001

Empirical evidence of correlated biases in dietary assessment instruments and its implications.

Multiple-day food records or 24-hour recalls are currently used as "reference" instruments to calibrate food frequency questionnaires (FFQs) and to adjust findings from nutritional epidemiologic studies for measurement error. The common adjustment is based on the critical requirements that errors in the reference instrument be independent of those in the FFQ and of true intake. When data on urinary nitrogen level, a valid reference biomarker for nitrogen intake, are used, evidence suggests that a dietary report reference instrument does not meet these requirements. In this paper, the authors introduce a new model that includes, for both the FFQ and the dietary report reference instrument, group-specific biases related to true intake and correlated person-specific biases. Data were obtained from a dietary assessment validation study carried out among 160 women at the Dunn Clinical Nutrition Center, Cambridge, United Kingdom, in 1988-1990. Using the biomarker measurements and dietary report measurements from this study, the authors compare the new model with alternative measurement error models proposed in the literature and demonstrate that it provides the best fit to the data. The new model suggests that, for these data, measurement error in the FFQ could lead to a 51% greater attenuation of true nutrient effect and the need for a 2.3 times larger study than would be estimated by the standard approach. The implications of the results for the ability of FFQ-based epidemiologic studies to detect important diet-disease associations are discussed.

Bias↗
PubMed2001

Efficient regression calibration for logistic regression in main study/internal validation study designs with an imperfect reference instrument.

An extension to the version of the regression calibration estimator proposed by Rosner et al. for logistic and other generalized linear regression models is given for main study/internal validation study designs. This estimator combines the information about the parameter of interest contained in the internal validation study with Rosner et al.'s regression calibration estimate, using a generalized inverse-variance weighted average. It is shown that the validation study selection model can be ignored as long as this model is jointly independent of the outcome and the incompletely observed covariates, conditional, at most, upon the surrogates and other completely observed covariates. In an extensive simulation study designed to follow a complex, multivariate setting in nutritional epidemiology, it is shown that with validation study sizes of 340 or more, this estimator appears to be asymptotically optimal in the sense that it is nearly unbiased and nearly as efficient as a properly specified maximum likelihood estimator. A modification to the regression calibration variance estimator which replaces the standard uncorrected logistic regression coefficient variance with the sandwich estimator to account for the possible misspecification of the logistic regression fit to the surrogate covariates in the main study, was also studied in this same simulation experiment. In this study, the alternative variance formula yielded results virtually identical to the original formula. A version of the proposed estimator is also derived for the case where the reference instrument, available only in the validation study, is imperfect but unbiased at the individual level and contains error that is uncorrelated with other covariates and with error in the surrogate instrument. Replicate measures are obtained in a subset of study participants. In this case it is shown that the validation study selection model can be ignored when sampling into the validation study depends, at most, only upon perfectly measured covariates. Two data sets, a study of fever in relation to occupational exposure to antineoplastics among hospital pharmacists and a study of breast cancer incidence in relation to dietary intakes of alcohol and vitamin A, adjusted for total energy intake, from the Nurses' Health Study, were analysed using these new methods. In these data, because the validation studies contained less than 200 observations and the events of interest were relatively rare, as is typical, the potential improvements offered by this new estimator were not apparent.

Adult↗
PubMed2001

Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model.

There is now general agreement that the etiology of proximal and distal colon cancers may differ, thus prompting renewed interest in understanding anatomical site-specific molecular mechanisms of tumor development. Using a 2x2x2 factorial design with male Sprague-Dawley rats (corn oil, fish oil; pectin, cellulose; plus or minus azoxymethane injection) we found a greater than 2-fold difference (P < 0.001) in tumor incidence proximally versus distally (prox/dist ratio: corn oil, 2.25; fish oil, 2.61). The purpose of the present study was to determine if the higher degree of proximal versus distal tumors in our model system could be accounted for by differences between these two sites in initial DNA damage, response to that damage or an effect of diet at one site but not the other. DNA damage was assessed by quantitative immunohistochemistry of O(6)-methylguanine adducts; repair by measurement of O(6)-methylguanine-DNA alkyltransferase and removal was determined by measurement of targeted apoptosis. Although overall initial DNA damage was similar at both sites, in the distal colon there was a greater expression of repair protein (P < 0.001) and a greater degree of targeted apoptosis (P < 0.0001). There was also a reduction in DNA damage in the distal colon of rats consuming fish oil. Together, these results suggest that the lower tumor incidence in the distal colon may be a result of the capacity to deal with initial DNA damage by the distal colon, as compared with the proximal colon. Therefore, the determination of site-specific mechanisms in tumor development is important because distinct strategies may be required to protect against cancer at different sites.

Adenocarcinoma↗
PubMed2001

Review times in statistical journals: tilting at windmills?

Using limited data, I argue that the review times in statistics are far too long for the field to keep pace with the rapidly changing environment in science. I note that statisticians do not appear to believe in statistics because data on the review process are not widely available to members of the profession. I suggest a few changes that could be made to speed up the review process, although it would appear that a change in our culture is required before the problem will be solved.

Biometry↗
PubMed2001

Covariate measurement error adjustment for matched case-control studies.

We propose a conditional scores procedure for obtaining bias-corrected estimates of log odds ratios from matched case-control data in which one or more covariates are subject to measurement error. The approach involves conditioning on sufficient statistics for the unobservable true covariates that are treated as fixed unknown parameters. For the case of Gaussian nondifferential measurement error, we derive a set of unbiased score equations that can then be solved to estimate the log odds ratio parameters of interest. The procedure successfully removes the bias in naive estimates, and standard error estimates are obtained by resampling methods. We present an example of the procedure applied to data from a matched case-control study of prostate cancer and serum hormone levels, and we compare its performance to that of regression calibration procedures.

Bias↗
PubMed2001

Combining datasets to predict the effects of regulation of environmental lead exposure in housing stock.

A model for children's blood lead concentrations as a function of environmental lead exposures was developed by combining two nationally representative sources of data that characterize the marginal distributions of blood lead and environmental lead with a third regional dataset that contains joint measures of blood lead and environmental lead. The complicating factor addressed in this article was the fact that methods for assessing environmental lead were different in the national and regional datasets. Relying on an assumption of transportability (that although the marginal distributions of blood lead and environmental lead may be different between the regional dataset and the nation as a whole, the joint relationship between blood lead and environmental lead is the same), the model makes use of a latent variable approach to estimate the joint distribution of blood lead and environmental lead nationwide.

Biometry↗
PubMed2001

Thyroid cancer following scalp irradiation: a reanalysis accounting for uncertainty in dosimetry.

In the 1940s and 1950s, over 20,000 children in Israel were treated for tinea capitis (scalp ringworm) by irradiation to induce epilation. Follow-up studies showed that the radiation exposure was associated with the development of malignant thyroid neoplasms. Despite this clear evidence of an effect, the magnitude of the dose-response relationship is much less clear because of probable errors in individual estimates of dose to the thyroid gland. Such errors have the potential to bias dose-response estimation, a potential that was not widely appreciated at the time of the original analyses. We revisit this issue, describing in detail how errors in dosimetry might occur, and we develop a new dose-response model that takes the uncertainties of the dosimetry into account. Our model for the uncertainty in dosimetry is a complex and new variant of the classical multiplicative Berkson error model, having components of classical multiplicative measurement error as well as missing data. Analysis of the tinea capitis data suggests that measurement error in the dosimetry has only a negligible effect on dose-response estimation and inference as well as on the modifying effect of age at exposure.

Biometry↗
PubMed2000

Score tests for familial correlation in genotyped-proband designs.

In the genotyped-proband design, a proband is selected based on an observed phenotype, the genotype of the proband is observed, and then the phenotypes of all first-degree relatives are obtained. The genotypes of these first-degree relatives are not observed. Gail et al. [(1999) Genet Epidemiol] discuss likelihood analysis of this design under the assumption that the phenotypes are conditionally independent of one another given the observed and unobserved genotypes. Li and Thompson [(1997) Biometrics 53:282-293] give an example where this assumption is suspect, thus suggesting that it is important to develop tests for conditional independence. In this paper, we develop a score test for the conditional independence assumption in models that might include covariates or observation of genotypes for some of the first degree relatives. The problem can be cast more generally as one of score testing in the presence of missing covariates. A standard analysis would require specifying a distribution for the covariates, which is not convenient and could lead to a lack of model-robustness. We show that by considering a natural conditional likelihood, and basing the score test on it, a simple analysis results. The methods are applied to a study of the penetrance for breast cancer of BRCA1 and BRCA2 mutations among Ashkenazi Jews.

Alleles↗
PubMed2000

Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint.

Phase II evaluation is a critical screening step in the development of new cancer treatments. Historically, anticancer agents have been cytotoxic; they kill existing cells. As such, the primary endpoint for phase II evaluation has been tumor response rate, the percentage of patients whose tumors shrink > 50%. Biotechnology has led to promising new anticancer agents that are cytostatic. In contrast to cytotoxics, these agents modulate tumor environments and/or cellular targets and are expected to delay tumor growth. Phase II evaluation of such agents may instead focus on failure-time endpoints, such as time to disease progression. We examine a phase II trial design that evaluates clinical benefit by comparing sequentially measured paired failure times within each treated patient. Clinical efficacy is defined by a hazard ratio. Assuming patients eligible for a phase II study of a new cytostatic agent have failed previous cancer treatment, their most recent prior time to progression interval, TTP(1), is uncensored. Time to progression after the cytostatic agent, TTP(2), may or may not be censored at analysis. The design is motivated by a "growth modulation index" (TTP(2)/TTP(1)) and the proposition that a cytostatic agent be considered effective if the index is greater than 1.33. A chi(2) test statistic is employed to evaluate the paired failure-time data (TTP(1), TTP(2)). The degree of correlation between the paired failure times is a key feature of this design. Power of the test was evaluated through simulation of trials. Assuming a null hazard ratio equal to 1.0, a trial designed to detect an alternative hazard ratio equal to 1.3, based on accrual of 25 patients/year for 2 years (50 patients total) and with an additional 2 years of follow-up, has 25%, 46%, and 83% power based on correlations of 0.3, 0.5 and 0.7, respectively. These results demonstrate efficiency of the trial design, given moderate to strong correlations between paired failure times.

Antineoplastic Agents↗
PubMed2000

On meta-analytic assessment of surrogate outcomes.

We discuss the strengths and weaknesses of the meta-analytic approach to estimating the effect of a new treatment on a true clinical outcome measure, T, from the effect of treatment on a surrogate response, S. The meta-analytic approach (see Daniels and Hughes (1997) 16, 1965-1982) uses data from a series of previous studies of interventions similar to the new treatment. The data are used to estimate relationships between summary measures of treatment effects on T and S that can be used to infer the magnitude of the effect of the new treatment on T from its effects on S. We extend the class of models to cover a broad range of applications in which the parameters define features of the marginal distribution of (T, S). We present a new bootstrap procedure to allow for the variability in estimating the distribution that governs the between-study variation. Ignoring this variability can lead to confidence intervals that are much too narrow. The meta-analytic approach relies on quite different data and assumptions than procedures that depend, for example, on the conditional independence, at the individual level, of treatment and T, given S (see Prentice (1989) 8, 431-440). Meta-analytic calculations in this paper can be used to determine whether a new study, based only on S, will yield estimates of the treatment effect on T that are precise enough to be useful. Compared to direct measurement on T, the meta-analytic approach has a number of limitations, including likely serious loss of precision and difficulties in defining the class of previous studies to be used to predict the effects on T for a new intervention.

Journal Article↗
PubMed2000

Random effects in censored ordinal regression: latent structure and Bayesian approach.

This paper discusses random effects in censored ordinal regression and presents a Gibbs sampling approach to fit the regression model. A latent structure and its corresponding Bayesian formulation are introduced to effectively deal with heterogeneous and censored ordinal observations. This work is motivated by the need to analyze interval-censored ordinal data from multiple studies in toxicological risk assessment. Application of our methodology to the data offers further support to the conclusions developed earlier using GEE methods yet provides additional insight into the uncertainty levels of the risk estimates.

Animals↗
PubMed2000

Conditional and unconditional categorical regression models with missing covariates.

We consider methods for analyzing categorical regression models when some covariates (Z) are completely observed but other covariates (X) are missing for some subjects. When data on X are missing at random (i.e., when the probability that X is observed does not depend on the value of X itself), we present a likelihood approach for the observed data that allows the same nuisance parameters to be eliminated in a conditional analysis as when data are complete. An example of a matched case-control study is used to demonstrate our approach.

Biometry↗
PubMed2000

Morphodensitometric analysis of protein kinase C beta(II) expression in rat colon: modulation by diet and relation to in situ cell proliferation and apoptosis.

We have recently demonstrated that overexpression of PKC beta(II) renders transgenic mice more susceptible to carcinogen-induced colonic hyperproliferation and aberrant crypt foci formation. In order to further investigate the ability of PKC beta(II) to modulate colonocyte cytokinetics, we determined the localization of PKC beta(II) with respect to cell proliferation and apoptosis along the entire colonic crypt axis following carcinogen and diet manipulation. Rats were provided diets containing either corn oil [containing n-6 polyunsaturated fatty acids (PUFA)] or fish oil (containing n-3 PUFA), cellulose (non-fermentable fiber) or pectin (fermentable fiber) and injected with azoxymethane (AOM) or saline. After 16 weeks, an intermediate time point when no macroscopic tumors are detected, colonic sections were utilized for immunohistochemical image analysis and immunoblotting. Cell proliferation was measured by incorporation of bromodeoxyuridine into DNA and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling. In the distal colon, PKC beta(II) staining was localized to the upper portion of the crypt. In comparison, proximal crypts had more (P < 0.05) staining in the lower tertile. AOM enhanced (P < 0.05) PKC beta(II) expression in all regions of the distal colonic crypt (upper, middle and lower tertiles). There was also an interaction (P < 0.05) between dietary fat and fiber on PKC beta(II) expression (corn/pectin > fish/cellulose, fish/pectin > corn/cellulose) in all regions of the distal colonic crypt. With respect to colonic cell kinetics, proliferation paralleled the increase in PKC beta(II) expression in carcinogen-treated animals. In contrast, apoptosis at the lumenal surface was inversely proportional to PKC beta(II) expression in the upper tertile. These results suggest that an elevation in PKC beta(II) expression along the crypt axis in the distal colon is linked to enhancement of cell proliferation and suppression of apoptosis, predictive intermediate biomarkers of tumor development. Therefore, select dietary factors may confer protection against colon carcinogenesis in part by blocking carcinogen-induced PKC beta(II) expression.

Animals↗
PubMed2000

Dietary fish oil reduces O6-methylguanine DNA adduct levels in rat colon in part by increasing apoptosis during tumor initiation.

There is epidemiological, clinical, and experimental evidence that dietary fish oil, containing n-3 polyunsaturated fatty acids, protects against colon tumor development. However, its effects on colonocytes in vivo remain poorly understood. Therefore, we investigated the ability of fish oil to modulate colonic methylation-induced DNA damage, repair, and deletion. Sprague Dawley rats were provided with complete diets containing either corn oil or fish oil (15% by weight). Animals were injected with azoxymethane, and the distal colon was removed 3, 6, 9, or 12 h later. Targeted apoptosis and DNA damage were assessed by cell position within the crypt using the terminal deoxynucleotidyl transferase-mediated nick end labeling assay and quantitative immunohistochemical analysis of O6-methylguanine adducts, respectively. Localization and expression of the alkyl group acceptor, O6-methylguanine-DNA-methyltransferase, was also determined. Lower levels of adducts were detected at 6, 9, and 12 h in fish oil- versus corn oil-fed animals (P < 0.05). In addition, fish oil supplementation had the greatest effect on apoptosis in the top one-third of the crypt, increasing the apoptotic index compared with corn oil-fed rats (P < 0.05). In the top one-third of the crypt, fish oil feeding caused an incremental stimulation of apoptosis as adduct level increased. In contrast, a negative correlation between apoptosis and adduct incidence occurred with corn oil feeding (P < 0.05). Diet had no main effect (all tertiles combined) on O6-methylguanine-DNA-methyltransferase expression over the time frame of the experiment. The enhancement of targeted apoptosis combined with the reduced formation of O6-methylguanine adducts may account, in part, for the observed protective effect of n-3 polyunsaturated fatty acids against experimentally induced colon cancer.

Analysis of Variance↗