The volume effect in irradiated mouse colorectum

Damage of the colorectum is the dose-limiting normal tissue complication following radiotherapy of prostate and cervical cancers. One approach for decreasing complications is to physically reduce the treatment volume. Mathematical models have been previously developed to describe the change in associated toxicity with a change in irradiated volume, i.e. the "volume effect", for serial-type normal tissues including the colorectum. The first goal of this thesis was to test the hypothesis that there would not be a threshold length in the development of obstruction after irradiation of mouse colorectum, as predicted by the Probability model of the volume effect. The second goal was to examine if there were differences in the threshold and in the incidence of colorectal obstruction after irradiation of two mouse strains, C57B1/6 (C57) and C3Hf/Kam (C3H), previously found to be fibrosis-prone and-resistant, respectively, after lung irradiation due, in part, to genetic differences. The hypothesis examined was that differences in incidence between strains were due to the differential expression of the fibrogenic cytokines $\rm TGF\beta$ and $\rm TNF\alpha.$ Various lengths of C57 and C3H mouse colorectum were irradiated and the incidence of colorectal obstruction was followed up to 15 months. A threshold length was observed for both mouse strains, in contradiction of model predictions. The mechanism of the threshold was epithelial regeneration after irradiation. C57 mice had significantly higher incidence of colorectal obstruction compared to C3H mice, especially at smaller irradiated lengths. Colorectal tissue was obtained at various times after irradiation and prepared for histology, immunohistochemistry and RNase protection assay for measurement of $\rm TGF\beta 1,$ 2, 3 and $\rm TNF\alpha$ mRNA. Distinct strain differences in the histological time of appearance and spatial locations of fibrosis were observed. However, there were no consistent strain difference in mRNA levels or immunolocalization for any of the cytokines examined. The data indicate the need for volume effect models that account for biologically important processes, such as the effect of epithelial regeneration after irradiation. As well, changes in fibrogenic cytokines at the mRNA level do not contribute to the strain difference in radiation-induced colorectal obstruction. ^

Bayesian joint modeling of longitudinal and survival data

The joint modeling of longitudinal and survival data is a new approach to many applications such as HIV, cancer vaccine trials and quality of life studies. There are recent developments of the methodologies with respect to each of the components of the joint model as well as statistical processes that link them together. Among these, second order polynomial random effect models and linear mixed effects models are the most commonly used for the longitudinal trajectory function. In this study, we first relax the parametric constraints for polynomial random effect models by using Dirichlet process priors, then three longitudinal markers rather than only one marker are considered in one joint model. Second, we use a linear mixed effect model for the longitudinal process in a joint model analyzing the three markers. In this research these methods were applied to the Primary Biliary Cirrhosis sequential data, which were collected from a clinical trial of primary biliary cirrhosis (PBC) of the liver. This trial was conducted between 1974 and 1984 at the Mayo Clinic. The effects of three longitudinal markers (1) Total Serum Bilirubin, (2) Serum Albumin and (3) Serum Glutamic-Oxaloacetic transaminase (SGOT) on patients' survival were investigated. Proportion of treatment effect will also be studied using the proposed joint modeling approaches. ^ Based on the results, we conclude that the proposed modeling approaches yield better fit to the data and give less biased parameter estimates for these trajectory functions than previous methods. Model fit is also improved after considering three longitudinal markers instead of one marker only. The results from analysis of proportion of treatment effects from these joint models indicate same conclusion as that from the final model of Fleming and Harrington (1991), which is Bilirubin and Albumin together has stronger impact in predicting patients' survival and as a surrogate endpoints for treatment. ^

Heart rate variability in response to pain stimulus in VLBW infants followed longitudinally during NICU stay.

The objective of this longitudinal study, conducted in a neonatal intensive care unit, was to characterize the response to pain of high-risk very low birth weight infants (<1,500 g) from 23 to 38 weeks post-menstrual age (PMA) by measuring heart rate variability (HRV). Heart period data were recorded before, during, and after a heel lanced or wrist venipunctured blood draw for routine clinical evaluation. Pain response to the blood draw procedure and age-related changes of HRV in low-frequency and high-frequency bands were modeled with linear mixed-effects models. HRV in both bands decreased during pain, followed by a recovery to near-baseline levels. Venipuncture and mechanical ventilation were factors that attenuated the HRV response to pain. HRV at the baseline increased with post-menstrual age but the growth rate of high-frequency power was reduced in mechanically ventilated infants. There was some evidence that low-frequency HRV response to pain improved with advancing PMA.

Assessing homogeneity in workplace exposure under stationary and non-stationary scenarios

In most epidemiological studies, historical monitoring data are scant and must be pooled to identify occupational groups with homogeneous exposures. Homogeneity of exposure is generally assessed in a group of workers who share a common job title or work in a common area. While published results suggest that the degree of homogeneity varies widely across job groups, less is known whether such variation differs across industrial sectors, classes of contaminants, or in the methods used to group workers. Relying upon a compilation of results presented in the literature, patterns of homogeneity among nearly 500 occupational groups of workers were evaluated on the basis of type of industry and agent. Additionally, effects of the characteristics of the sampling strategy on estimated indicators of homogeneity of exposure were assessed. ^ Exposure profiles for occupational groups of workers have typically been assessed under the assumption of stationarity, i.e., the mean exposure level and variance of the distribution that describes the underlying population of exposures are constant over time. Yet, the literature has shown that occupational exposures have declined in the last decades. This renders traditional methods for the description of exposure profiles inadequate. Thus, work was needed to develop appropriate methods to assess homogeneity for groups of workers whose exposures have changed over time. A study was carried out applying mixed effects models with a term for temporal trend to appropriately describe exposure profiles of groups of workers in the nickel-producing industry over a 20-year period. Using a sub-set of groups of nickel-exposed workers, another study was conducted to develop and apply a framework to evaluate the assumption of stationarity of the variances in the presence of systematic changes in exposure levels over time. ^

Understanding disparities in emergency department visits for asthma

Asthma is the most common chronic disorder in childhood, affecting an estimated 6.2 million children under 18 years (1). The purpose of this study was to look at individual- and community-level characteristics simultaneously to examine and explain the factors that contribute to the use of emergency department services by children 18 years old or less and to determine if there was an association between air quality and ED visits in the same population, from 2005-2007 in Houston/Harris County. Data were collected from the Houston Safety Net Hospital Emergency Department Use Study and the 2000 US Census. Bivariate and multivariate logistic regression models and mixed effects models were used to analyze data that was collected during the study period.^ There were 704,902 ED visits made by children 18 and younger, who were living in Houston from January 1, 2005 to December 31, 2007. Of those, 19,098 had a primary discharge diagnosis of asthma. Asthma ED visits varied by season, with proportions of ED visits for asthma highest from September-December. African-American children were 2.6 (95% CI, 2.43-2.66) times more likely to have an ED visit for asthma compared to White children. Poverty, single parent headed households, and younger age all a greater likelihood of having gone to the ED for asthma treatment. Compared to Whites living in lightly-monitored pollution areas, African-Americans and Hispanics living in heavily monitored areas were 1.15 (95% CI, 1.04-1.28) times more likely to have an ED visit for asthma.^ Race and poverty seem to account for a large portion of the disparities in ED use found among children. This was true even after accounting for multiple individual- and community-level variables. These results suggest that racial disparities in asthma continue to pose risks for African American children, and they point to the need for additional research into potential explanations and remedies. Programs to reduce inappropriate ED use must be sensitive to an array of complex socioeconomic issues within minority and income populations. ^

Parental acculturation and adolescent HPV uptake among Hispanics: Results from the California Health Interview Survey

Background. The Centers for Disease Control and Prevention (CDC), the American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) all recommend the HPV vaccine for girls 11-12. The vaccine has the potential to reduce cervical cancer disparities if it is used by populations that do not participate in screening. Evidence suggests that incidence and mortality are higher among Hispanic women compared to non-Hispanic white women because they do not participate in screening. Past literature has found that acculturation has a mixed effect on cervical cancer screening and immunization. Little is known about whether parental acculturation is associated with adolescent HPV vaccine uptake among Hispanics and the mechanisms through which acculturation may affect vaccine uptake.^ Aims. To examine the association between parental acculturation and adolescent HPV uptake among Hispanics in California and test the structural hypothesis of acculturation by determining if socioeconomic status (SES) and health care access mediate the association between acculturation and HPV vaccine uptake.^ Methods. Cross-sectional data from the 2007 California Health Interview Survey (CHIS) were used for bivariate and multivariate logistic regression analyses. The sample used for analysis included 1,090 Hispanic parents, with a daughter age 11-17, who answered questions about the HPV vaccine. Outcome variable of interest was HPV vaccine uptake (≥1dose). Independent variables of interest were language spoken at home (a proxy variable for acculturation), household income (percent of federal poverty level), education level, and health care access (combined measure of health insurance coverage and usual source of care).^ Results. Parents who spoke only English or English and Spanish in the home were more likely to get the HPV vaccine for their daughter than parents who only spoke Spanish (Odds Ratio [OR]: 0.55, 95% Confidence Interval [CI]: 0.31-0.98). When SES and health care access variables were added to the logistic regression model, the association between language acculturation and HPV vaccine uptake became non-significant (OR: 0.68, 95% CI: 0.35-1.29). Both income and health care access were associated with uptake. Parents with lower income or who did not have insurance and a usual source of care were less likely to have a vaccinated daughter.^ Discussion. Socioeconomic status and health care access have a more proximal effect on HPV vaccine uptake than parental language acculturation among Hispanics in California.^ Conclusion. This study found support for the structural hypothesis of acculturation and suggest that interventions focus on informing low SES parents who lack access to health care about programs that provide free HPV vaccines.^

The role of cardiorespiratory fitness and weight status on 24-hr ambulatory blood pressure among adolescents

BACKGROUND: This observational research study investigated the association of cardiorespiratory fitness and weight status with repeated measures of 24-hr ambulatory blood pressure (24-hr ABP). Little is known about these associations and few data exist examining the interaction between cardiorespiratory fitness and weight status and the contributions of each on 24-hr ABP in youth. ^ METHODS: This research study used secondary analysis data from the "Adolescent Blood Pressure and Anger: Ethnic Differences" study. This current study sample included 374 African-American, Anglo-American, and Mexican-American adolescents 11-16 years of age. Mixed-effects models were used for testing the relationship between weight status and cardiorespiratory fitness and repeated measures of ambulatory blood pressure over 24 hours (24-hr ABP). Weight status was categorized into "normal weight" (BMI<85th percentile), "overweight" (85th≤BMI<95th), and "obese" (BMI≥95th). Cardiorespiratory fitness, determined by heart rate recovery (HRR), was defined as the difference between heart rate at peak exercise and heart rate at two minutes post-exercise, as measured by a height-adjusted step test and stratified into two groups: low and high fitness, using a median split. Ambulatory blood pressure (ABP) was monitored for a 24-hr period on a school day using the Spacelabs ambulatory monitor (Model 90207). Blood pressure and heart rate were recorded at 30 minute intervals throughout the day of recording and at 60 minute intervals during sleep. ^ RESULTS: No significant associations were found between weight status and mean 24-hr systolic blood pressure (SBP) or mean arterial pressure (MAP). A significant and inverse association between weight status and mean 24-hr diastolic blood pressure (DBP) was revealed. Cardiorespiratory fitness was significantly and inversely associated with mean 24-hr ABP. High fitness adolescents had significantly lower mean 24-hr SPB, DBP, and MAP measurements than low fitness adolescents. Compared to low fitness adolescents, high fitness adolescents had 1.90 mmHg, 1.16 mmHg, and 1.68 mmHg lower mean 24-hr SBP, DBP, and MAP, respectively. Additionally, high fitness appeared to afford protection from higher mean 24-hr SBP and MAP, irrespective of weight status. Among normal weight adolescents, low fitness resulted in higher mean 24-hr SBP and MAP, compared to their fit counterparts. Among adolescents categorized as high fitness, increasing weight status did not appear to result in higher mean 24-hr SBP or MAP. Cardiorespiratory fitness, rather than weight status, appeared to be a more dominant predictor of mean 24-hr SBP and MAP. ^ CONCLUSIONS: To our knowledge, this research is the first study to investigate the independent and combined contributions of cardiorespiratory fitness and weight status on 24-hr ABP, all objectively measured. The results of this study may potentially guide and inform future research. It appears that early cardiovascular disease (CVD) prevention should focus on improving cardiorespiratory fitness levels among all adolescents, particularly those adolescents least fit, regardless of their weight status, while obesity prevention efforts continue.^

Effect of nonnormal random components on level and power in group-randomized trials

The use of group-randomized trials is particularly widespread in the evaluation of health care, educational, and screening strategies. Group-randomized trials represent a subset of a larger class of designs often labeled nested, hierarchical, or multilevel and are characterized by the randomization of intact social units or groups, rather than individuals. The application of random effects models to group-randomized trials requires the specification of fixed and random components of the model. The underlying assumption is usually that these random components are normally distributed. This research is intended to determine if the Type I error rate and power are affected when the assumption of normality for the random component representing the group effect is violated. ^ In this study, simulated data are used to examine the Type I error rate, power, bias and mean squared error of the estimates of the fixed effect and the observed intraclass correlation coefficient (ICC) when the random component representing the group effect possess distributions with non-normal characteristics, such as heavy tails or severe skewness. The simulated data are generated with various characteristics (e.g. number of schools per condition, number of students per school, and several within school ICCs) observed in most small, school-based, group-randomized trials. The analysis is carried out using SAS PROC MIXED, Version 6.12, with random effects specified in a random statement and restricted maximum likelihood (REML) estimation specified. The results from the non-normally distributed data are compared to the results obtained from the analysis of data with similar design characteristics but normally distributed random effects. ^ The results suggest that the violation of the normality assumption for the group component by a skewed or heavy-tailed distribution does not appear to influence the estimation of the fixed effect, Type I error, and power. Negative biases were detected when estimating the sample ICC and dramatically increased in magnitude as the true ICC increased. These biases were not as pronounced when the true ICC was within the range observed in most group-randomized trials (i.e. 0.00 to 0.05). The normally distributed group effect also resulted in bias ICC estimates when the true ICC was greater than 0.05. However, this may be a result of higher correlation within the data. ^

Evaluation of the Hosmer -Lemeshow global goodness -of-fit statistic for mixed variable logistic regression models

The performance of the Hosmer-Lemeshow global goodness-of-fit statistic for logistic regression models was explored in a wide variety of conditions not previously fully investigated. Computer simulations, each consisting of 500 regression models, were run to assess the statistic in 23 different situations. The items which varied among the situations included the number of observations used in each regression, the number of covariates, the degree of dependence among the covariates, the combinations of continuous and discrete variables, and the generation of the values of the dependent variable for model fit or lack of fit.^ The study found that the $\rm\ C$g* statistic was adequate in tests of significance for most situations. However, when testing data which deviate from a logistic model, the statistic has low power to detect such deviation. Although grouping of the estimated probabilities into quantiles from 8 to 30 was studied, the deciles of risk approach was generally sufficient. Subdividing the estimated probabilities into more than 10 quantiles when there are many covariates in the model is not necessary, despite theoretical reasons which suggest otherwise. Because it does not follow a X$\sp2$ distribution, the statistic is not recommended for use in models containing only categorical variables with a limited number of covariate patterns.^ The statistic performed adequately when there were at least 10 observations per quantile. Large numbers of observations per quantile did not lead to incorrect conclusions that the model did not fit the data when it actually did. However, the statistic failed to detect lack of fit when it existed and should be supplemented with further tests for the influence of individual observations. Careful examination of the parameter estimates is also essential since the statistic did not perform as desired when there was moderate to severe collinearity among covariates.^ Two methods studied for handling tied values of the estimated probabilities made only a slight difference in conclusions about model fit. Neither method split observations with identical probabilities into different quantiles. Approaches which create equal size groups by separating ties should be avoided. ^