Biomedical subjects

Raymond J Carroll

Publications and source records attributed to Raymond J Carroll.

13 recordsLinked to original sources

PubMed2003

Dietary fish oil reduces oxidative DNA damage in rat colonocytes.

Prolonged generation of reactive oxygen species by inflammatory mediators can induce oxidative DNA damage (8-oxodG formation), potentially resulting in intestinal tumorigenesis. Fish oil (FO), compared to corn oil (CO), has been shown to downregulate inflammation and upregulate apoptosis targeted at damaged cells. We hypothesized FO could protect the intestine against 8-oxodG formation during dextran sodium sulfate- (DSS-) induced inflammation. We provided 60 rats with FO- or CO-supplemented diets for 2 weeks with or without 3% DSS in drinking water for 48 h. Half the treated rats received 48 additional h of untreated water before termination. Due to DSS treatment, the intestinal epithelium had higher levels of 8-oxodG (p =.04), induction of repair enzyme OGG1 mRNA (p =.02), and higher levels of apoptosis at the top of colonic crypts (p =.01) and in surface cells (p <.0001). FO-fed rats, compared to CO, had lower levels of 8-oxodG (p =.05) and increased apoptosis (p =.04) in the upper crypt region; however, FO had no significant effect on OGG1 mRNA. We conclude that FO protects intestinal cells against oxidative DNA damage in part via deletion mechanisms.

Animals↗

PubMed2003

Structure of dietary measurement error: results of the OPEN biomarker study.

Multiple-day food records or 24-hour dietary recalls (24HRs) are commonly used as "reference" instruments to calibrate food frequency questionnaires (FFQs) and to adjust findings from nutritional epidemiologic studies for measurement error. Correct adjustment requires that the errors in the adopted reference instrument be independent of those in the FFQ and of true intake. The authors report data from the Observing Protein and Energy Nutrition (OPEN) Study, conducted from September 1999 to March 2000, in which valid reference biomarkers for energy (doubly labeled water) and protein (urinary nitrogen), together with a FFQ and 24HR, were observed in 484 healthy volunteers from Montgomery County, Maryland. Accounting for the reference biomarkers, the data suggest that the FFQ leads to severe attenuation in estimated disease relative risks for absolute protein or energy intake (a true relative risk of 2 would appear as 1.1 or smaller). For protein adjusted for energy intake by using either nutrient density or nutrient residuals, the attenuation is less severe (a relative risk of 2 would appear as approximately 1.3), lending weight to the use of energy adjustment. Using the 24HR as a reference instrument can seriously underestimate true attenuation (up to 60% for energy-adjusted protein). Results suggest that the interpretation of findings from FFQ-based epidemiologic studies of diet-disease associations needs to be reevaluated.

Adult↗

PubMed2003

Assessing and interpreting treatment effects in longitudinal clinical trials with missing data.

Treatment effects are often evaluated by comparing change over time in outcome measures; however, valid analyses of longitudinal data can be problematic, particularly if some data are missing. For decades, the last observation carried forward (LOCF) approach has been a common method of handling missing data. Considerable advances in statistical methodology and our ability to implement those methods have been made in recent years. Thus, it is appropriate to reconsider analytic approaches for longitudinal data. This review examines the following from a clinical perspective: 1) the characteristics of missing data that influence analytic choices; 2) the attributes of common methods of handling missing data; and 3) the use of the data characteristics and the attributes of the various methods, along with empirical evidence, to develop a robust approach for the analysis and interpretation of data from longitudinal clinical trials. We propose that, in many settings, the primary efficacy analysis should use a repeated measures, likelihood-based, mixed-effects modeling approach, with LOCF used as a secondary, composite measure of efficacy, safety, and tolerability. We illustrate how repeated-measures analyses can be used to enhance decision-making, and we review the caveats that remain regarding the use of LOCF as a composite measure.

Analysis of Variance↗

PubMed2003

Assessing response profiles from incomplete longitudinal clinical trial data under regulatory considerations.

Treatment effects are often evaluated by comparing change over time in outcome measures. However, valid analyses of longitudinal data can be problematic, particularly when some data are missing for reasons related to the outcome. In choosing the primary analysis for confirmatory clinical trials, regulatory agencies have for decades favored the last observation carried forward (LOCF) approach for imputing missing values. Many advances in statistical methodology, and also in our ability to implement those methods, have been made in recent years. The characteristics of data from acute phase clinical trials can be exploited to develop an appropriate analysis for assessing response profiles in a regulatory setting. These data characteristics and regulatory considerations will be reviewed. Approaches for handling missing data are compared along with options for modeling time effects and correlations between repeated measurements. Theory and empirical evidence are utilized to support the proposal that likelihood-based mixed-effects model repeated measures (MMRM) approaches, based on the missing at random assumption, provide superior control of Type I and Type II errors when compared with the traditional LOCF approach, which is based on the more restrictive missing completely at random assumption. It is further reasoned that in acute phase clinical trials, unstructured modeling of time trends and within-subject error correlations may be preferred.

Clinical Trials as Topic↗

PubMed2003

The relationship between virologic and immunologic responses in AIDS clinical research using mixed-effects varying-coefficient models with measurement error.

In this article we study the relationship between virologic and immunologic responses in AIDS clinical trials. Since plasma HIV RNA copies (viral load) and CD4+ cell counts are crucial virologic and immunologic markers for HIV infection, it is important to study their relationship during HIV/AIDS treatment. We propose a mixed-effects varying-coefficient model based on an exploratory analysis of data from a clinical trial. Since both viral load and CD4+ cell counts are subject to measurement error, we also consider the measurement error problem in covariates in our model. The regression spline method is proposed for inference for parameters in the proposed model. The regression spline method transforms the unknown nonparametric components into parametric functions. It is relatively simple to implement using readily available software, and parameter inference can be developed from standard parametric models. We apply the proposed models and methods to an AIDS clinical study. From this study, we find an interesting relationship between viral load and CD4+ cell counts during antiviral treatments. Biological interpretations and clinical implications are discussed.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Fisher Lecture: the 2002 R. A. Fisher lecture: dedicated to the memory of Shanti S. Gupta. Variances are not always nuisance parameters.

In classical problems, e.g., comparing two populations, fitting a regression surface, etc., variability is a nuisance parameter. The term "nuisance parameter" is meant here in both the technical and the practical sense. However, there are many instances where understanding the structure of variability is just as central as understanding the mean structure. The purpose of this article is to review a few of these problems. I focus in particular on two issues: (a) the determination of the validity of an assay; and (b) the issue of the power for detecting health effects from nutrient intakes when the latter are measured by food frequency questionnaires. I will also briefly mention the problems of variance structure in generalized linear mixed models, robust parameter design in quality technology, and the signal in microarrays. In these and other problems, treating variance structure as a nuisance instead of a central part of the modeling effort not only leads to inefficient estimation of means, but also to misleading conclusions.

Analysis of Variance↗

PubMed2003

Fish oil enhances targeted apoptosis during colon tumor initiation in part by downregulating Bcl-2.

We have shown that fish oil is protective against colon tumorigenesis, primarily by upregulating apoptosis. Production of prostaglandin E2 (PGE2) in colon cancer cells by cyclooxygenase (COX)-I and -II is known to inhibit apoptosis by induction of bcl-2. Because we have shown that fish oil downregulates PGE2 and COX-II, we hypothesized that this upregulation of apoptosis would be coincident with a downregulation of bcl-2. Bcl-2 was localized within the colonic crypt by quantitative immunohistochemistry (IHC), and scraped colonic mucosa was used for immunoblot analysis of bcl-2. The tissue used for bcl-2 analysis was from the rats used to determine apoptosis. Briefly, tissues were collected from rats consuming diets containing either corn oil or fish oil at 3, 6, 9, and 12 h after carcinogen injection. The correlation between bcl-2 and apoptosis was also determined. Bcl-2 expression decreased until 9 h (P < 0.05), whereas apoptosis increased until 9 h (P < 0.01). Bcl-2 expression and apoptosis were negatively correlated in both the proximal (P < 0.05) and distal colon (P < 0.005). Fish oil decreased bcl-2 expression (P < 0.05) and increased apoptosis (P < 0.05) in the top third of the crypt in the distal colon. In conclusion, one pathway by which fish oil may mediate apoptosis and thus protect against colon tumorigenesis is by downregulation of anti-apoptotic bcl-2.

Analysis of Variance↗

PubMed2002

Effect heterogeneity by a matching covariate in matched case-control studies: a method for graphs-based representation.

The authors describe a method for assessing and characterizing effect heterogeneity related to a matching covariate in case-control studies, using an example from veterinary medicine. Data are from a case-control study conducted in Texas during 1997-1998 of 498 pairs of horses with colic and their controls. Horses were matched by veterinarian and by month of examination. The number of matched pairs of cases and controls varied by veterinarian. The authors demonstrate that there is effect heterogeneity related to this characteristic (i.e., cluster size of veterinarians) for the association of colic with certain covariates, using a moving average approach to conditional logistic regression and graphs-based methods. The method described in this report can be applied to examining effect heterogeneity (or effect modification) by any ordered categorical or continuous covariates for which cases have been matched with controls. The method described enables one to understand the pattern of variation across ordered categorical or continuous matching covariates and allows for any shape for this pattern. This method applies to effect modification when causality might be reasonably assumed.

Animals↗

PubMed2002

Increased risk of early-stage breast cancer related to consumption of sweet foods among women less than age 45 in the United States.

OBJECTIVES: To evaluate the associations of dietary macronutrients, food groups, and eating patterns with risk of breast cancer in a population-based case-control study. METHODS: In this study among women 20-44 years of age, 568 cases with breast cancer and 1451 population-based controls were included. They completed a detailed in-person interview, a self-administered food-frequency questionnaire and were measured for anthropometric indices. Logistic regression was used to estimate odds ratios (OR) and their 95% confidence intervals (CI) of breast cancer, adjusted for age, study site, race, education, alcohol consumption, oral contraceptive usage, smoking status, and body mass index. RESULTS: There was no association between breast cancer risk and intake of calories, macronutrients, or types of fat. Risk of breast cancer was unrelated to intakes of a variety of food groups, including red meats, dairy, high-fat snacks and desserts, or foods high in animal fat. Increased risk was observed for high intake of a food group composed of sweet items, particularly sodas and desserts. Risk increased linearly with percent of calories from sweets and frequency of sweets intake. Consumption of sweets 9.8 or more times per week compared with <2.8 times per week was associated with an adjusted OR of 1.32 (95% CI = 1.0-1.8). This association did not appear to be due to the high-fat foods or carbonated beverages that comprised the food group. Compared with women reporting one or two meals and snacks per day, reduced risks were noted for women reporting six or more (OR = 0.69, 95% CI = 0.4-1.1). CONCLUSIONS: These data suggest a modest relationship between intakes of sweet items with risk of in-situ and localized breast cancer in young women. This relation is consistent with the hypothesized link of high insulin exposure and risk of breast cancer. There was some suggestion that women who ate many times during the day were at reduced risk of disease, which is also consistent with an insulin-related mechanism.

Adult↗

PubMed2002

Bias in dietary-report instruments and its implications for nutritional epidemiology.

OBJECTIVE: To evaluate measurement error structure in dietary assessment instruments and to investigate its implications for nutritional studies, using urinary nitrogen excretion as a reference biomarker for protein intake. DESIGN: The dietary assessment methods included different food-frequency questionnaires (FFQs) and such conventional dietary-report reference instruments as a series of 24-hour recalls, 4-day weighed food records or 7-day diaries. SETTING: Six original pilot validation studies within the European Prospective Investigation of Cancer (EPIC), and two validation studies conducted by the British Medical Research Council (MRC) within the Norfolk cohort that later joined as a collaborative component cohort of EPIC. SUBJECTS: A sample of approximately 100 to 200 women and men, aged 35-74 years, from each of eight validation studies. RESULTS: In assessing protein intake, all conventional dietary-report reference methods violated the critical requirements for a valid reference instrument for evaluating, and adjusting for, dietary measurement error in an FFQ. They displayed systematic bias that depended partly on true intake and partly was person-specific, correlated with person-specific bias in the FFQ. Using the dietary-report methods as reference instruments produced substantial overestimation (up to 230%) of the FFQ correlation with true usual intake and serious underestimation (up to 240%) of the degree of attenuation of FFQ-based log relative risks. CONCLUSION: The impact of measurement error in dietary assessment instruments on the design, analysis and interpretation of nutritional studies may be much greater than has been previously estimated, at least regarding protein intake.

Adult↗

PubMed2002

A Bayesian analysis of colonic crypt structure and coordinated response to carcinogen exposure incorporating missing crypts.

This paper is concerned with modeling the architecture of colonic crypts and the implications of this modeling for understanding possible coordinated response of carcinogen-induced DNA damage between various regions of the colon. The methods we develop to address these two issues are applied to a particular important example in colon carcinogenesis. We cast the problem as an unusual and not previously studied hierarchical mixed-effects model characterized by completely missing covariates in units at a structurally base level, except for some randomly selected units. Information concerning the missing covariates is available through certain known ordering constraints and surrogate measures. Our methods use Bayesian machinery. We exploit the biological structure of this problem to generate the missing covariates simultaneously and efficiently at the base levels, as opposed to the naive practice of generating units at the base levels one-at-a-time with Metropolis-Hastings steps. We apply our methods to show that different regions of the colon have different architectures, and to estimate an important but non-standard function that measures the interrelationship of DNA damage mechanisms in different regions of the colon.

Journal Article↗

PubMed2002

Fish oil increases mitochondrial phospholipid unsaturation, upregulating reactive oxygen species and apoptosis in rat colonocytes.

We have shown that a combination of fish oil (high in n-3 fatty acids) with the butyrate-producing fiber pectin, upregulates apoptosis in colon cells exposed to the carcinogen azoxymethane, protecting against colon tumor development. We now hypothesize that n-3 fatty acids prime the colonocytes such that butyrate can initiate apoptosis. To test this, 30 Sprague-Dawley rats were provided with diets differing in the fatty acid composition (corn oil, fish oil or a purified fatty acid ethyl ester diet). Intact colon crypts were exposed ex vivo to butyrate, and analyzed for reactive oxygen species (ROS), mitochondrial membrane potential (MMP), translocation of cytochrome C to the cytosol, and caspase-3 activity (early events in apoptosis). The fatty acid composition of the three major mitochondrial phospholipids was also determined, and an unsaturation index calculated. The unsaturation index in cardiolipin was correlated with ROS levels (R = 0.99; P = 0.02). When colon crypts from fish oil and FAEE-fed rats were exposed to butyrate, MMP decreased (P = 0.041); and translocation of cytochrome C to the cytosol (P = 0.037) and caspase-3 activation increased (P = 0.032). The data suggest that fish oil may prime the colonocytes for butyrate-induced apoptosis by enhancing the unsaturation of mitochondrial phospholipids, especially cardiolipin, resulting in an increase in ROS and initiating apoptotic cascade.

Animals↗

PubMed2002

DNA microarray experiments: biological and technological aspects.

DNA microarray technologies, such as cDNA and oligonucleotide microarrays, promise to revolutionize biological research and further our understanding of biological processes. Due to the complex nature and sheer amount of data produced from microarray experiments, biologists have sought the collaboration of experts in the analytical sciences, including statisticians, among others. However, the biological and technical intricacies of microarray experiments are not easily accessible to analytical experts. One aim for this review is to provide a bridge to some of the relevant biological and technical aspects involved in microarray experiments. While there is already a large literature on the broad applications of the technology, basic research on the technology itself and studies to understand process variation remain in their infancy. We emphasize the importance of basic research in DNA array technologies to improve the reliability of future experiments.

Animals↗