Risk factors for encephalitis and death from West Nile virus infection: An analysis of hospitalized cases in Houston, Texas from 2002--2008

We conducted a nested case-control study to determine the significant risk factors for developing encephalitis from West Nile virus (WNV) infection. The purpose of this research project was to expand the previously published Houston study of 2002–2004 patients to include data on Houston patients from four additional years (2005–2008) to determine if there were any differences in risk factors shown to be associated with developing the more severe outcomes of WNV infection, encephalitis and death, by having this larger sample size. A re-analysis of the risk factors for encephalitis and death was conducted on all of the patients from 2002–2008 and was the focus of this proposed research. This analysis allowed for the determination to be made that there are differences in the outcome in the risk factors for encephalitis and death with an increased sample size. Retrospective medical chart reviews were completed for the 265 confirmed WNV hospitalized patients; 153 patients had encephalitis (WNE), 112 had either viral syndrome with fever (WNF) or meningitis (WNM); a total of 22 patients died. Univariate logistic regression analyses on demographic, comorbidities, and social risk factors was conducted in a similar manner as in the previously conducted study to determine the risk factors for developing encephalitis from WNV. A multivariate model was developed by using model building strategies for the multivariate logistic regression analysis. The hypothesis of this study was that there would be additional risk factors shown to be significant with the increase in sample size of the dataset. This analysis with a greater sample size and increased power supports the hypothesis in that there were additional risk factors shown to be statistically associated with the more severe outcomes of WNV infection (WNE or death). Based on univariate logistic regression results, these data showed that even though age of 20–44 years was statistically significant as a protecting effect for developing WNE in the original study, the expanded sample lacked significance. This study showed a significant WNE risk factor to be chronic alcohol abuse, when it was not significant in the original analysis. Other WNE risk factors identified in this analysis that showed to be significant but were not significant in the original analysis were cancer not in remission > 5 years, history of stroke, and chronic renal disease. When comparing the two analyses with death as an outcome, two risk factors that were shown to be significant in the original analysis but not in the expanded dataset analysis were diabetes mellitus and immunosuppression. Three risk factors shown to be significant in this expanded analysis but were not significant in the original study were illicit drug use, heroin or opiate use, and injection drug use. However, with the multiple logistic regression models, the same independent risk factors for developing encephalitis of age and history of hypertension including drug induced hypertension were consistent in both studies.^

Secondary data analysis of a pilot study of use of an instructional video for dietary assessment

Introduction. Food frequency questionnaires (FFQ) are used study the association between dietary intake and disease. An instructional video may potentially offer a low cost, practical method of dietary assessment training for participants thereby reducing recall bias in FFQs. There is little evidence in the literature of the effect of using instructional videos on FFQ-based intake. Objective. This analysis compared the reported energy and macronutrient intake of two groups that were randomized either to watch an instructional video before completing an FFQ or to view the same instructional video after completing the same FFQ. Methods. In the parent study, a diverse group of students, faculty and staff from Houston Community College were randomized to two groups, stratified by ethnicity, and completed an FFQ. The "video before" group watched an instructional video about completing the FFQ prior to answering the FFQ. The "video after" group watched the instructional video after completing the FFQ. The two groups were compared on mean daily energy (Kcal/day), fat (g/day), protein (g/day), carbohydrate (g/day) and fiber (g/day) intakes using descriptive statistics and one-way ANOVA. Demographic, height, and weight information was collected. Dietary intakes were adjusted for total energy intake before the comparative analysis. BMI and age were ruled out as potential confounders. Results. There were no significant differences between the two groups in mean daily dietary intakes of energy, total fat, protein, carbohydrates and fiber. However, a pattern of higher energy intake and lower fiber intake was reported in the group that viewed the instructional video before completing the FFQ compared to those who viewed the video after. Discussion. Analysis of the difference between reported intake of energy and macronutrients showed an overall pattern, albeit not statistically significant, of higher intake in the video before versus the video after group. Application of instructional videos for dietary assessment may require further research to address the validity of reported dietary intakes in those who are randomized to watch an instructional video before reporting diet compared to a control groups that does not view a video.^

Secondary data analysis of lead screening compliance in high-risk children

Introduction. Despite the ban of lead-containing gasoline and paint, childhood lead poisoning remains a public health issue. Furthermore, a Medicaid-eligible child is 8 times more likely to have an elevated blood lead level (EBLL) than a non-Medicaid child, which is the primary reason for the early detection lead screening mandate for ages 12 and 24 months among the Medicaid population. Based on field observations, there was evidence that suggested a screening compliance issue. Objective. The purpose of this study was to analyze blood lead screening compliance in previously lead poisoned Medicaid children and test for an association between timely lead screening and timely childhood immunizations. The mean months between follow-up tests were also examined for a significant difference between the non-compliant and compliant lead screened children. Methods. Access to the surveillance data of all childhood lead poisoned cases in Bexar County was granted by the San Antonio Metropolitan Health District. A database was constructed and analyzed using descriptive statistics, logistic regression methods and non-parametric tests. Lead screening at 12 months of age was analyzed separately from lead screening at 24 months. The small portion of the population who were also related were included in one analysis and removed from a second analysis to check for significance. Gender, ethnicity, age of home, and having a sibling with an EBLL were ruled out as confounders for the association tests but ethnicity and age of home were adjusted in the nonparametric tests. Results. There was a strong significant association between lead screening compliance at 12 months and childhood immunization compliance, with or without including related children (p<0.00). However, there was no significant association between the two variables at the age of 24 months. Furthermore, there was no significant difference between the median of the mean months of follow-up blood tests among the non-compliant and compliant lead screened population for at the 12 month screening group but there was a significant difference at the 24 month screening group (p<0.01). Discussion. Descriptive statistics showed that 61% and 56% of the previously lead poisoned Medicaid population did not receive their 12 and 24 month mandated lead screening on time, respectively. This suggests that their elevated blood lead level may have been diagnosed earlier in their childhood. Furthermore, a child who is compliant with their lead screening at 12 months of age is 2.36 times more likely to also receive their childhood immunizations on time compared to a child who was not compliant with their 12 month screening. Even though there was no statistical significant association found for the 24 month group, the public health significance of a screening compliance issue is no less important. The Texas Medicaid program needs to enforce lead screening compliance because it is evident that there has been no monitoring system in place. Further recommendations include a need for an increased focus on parental education and the importance of taking their children for wellness exams on time.^

Bayesian inference and its application to meta-analysis of epidemiologic data

In Part One, the foundations of Bayesian inference are reviewed, and the technicalities of the Bayesian method are illustrated. Part Two applies the Bayesian meta-analysis program, the Confidence Profile Method (CPM), to clinical trial data and evaluates the merits of using Bayesian meta-analysis for overviews of clinical trials.^ The Bayesian method of meta-analysis produced similar results to the classical results because of the large sample size, along with the input of a non-preferential prior probability distribution. These results were anticipated through explanations in Part One of the mechanics of the Bayesian approach. ^

BEST SUBSET SELECTION FOR CATEGORICAL DATA

When choosing among models to describe categorical data, the necessity to consider interactions makes selection more difficult. With just four variables, considering all interactions, there are 166 different hierarchical models and many more non-hierarchical models. Two procedures have been developed for categorical data which will produce the "best" subset or subsets of each model size where size refers to the number of effects in the model. Both procedures are patterned after the Leaps and Bounds approach used by Furnival and Wilson for continuous data and do not generally require fitting all models. For hierarchical models, likelihood ratio statistics (G('2)) are computed using iterative proportional fitting and "best" is determined by comparing, among models with the same number of effects, the Pr((chi)(,k)('2) (GREATERTHEQ) G(,ij)('2)) where k is the degrees of freedom for ith model of size j. To fit non-hierarchical as well as hierarchical models, a weighted least squares procedure has been developed.^ The procedures are applied to published occupational data relating to the occurrence of byssinosis. These results are compared to previously published analyses of the same data. Also, the procedures are applied to published data on symptoms in psychiatric patients and again compared to previously published analyses.^ These procedures will make categorical data analysis more accessible to researchers who are not statisticians. The procedures should also encourage more complex exploratory analyses of epidemiologic data and contribute to the development of new hypotheses for study. ^

THE IMPLEMENTATION OF FEDERAL FAMILY PLANNING POLICY: AN ANALYSIS OF FACTORS AFFECTING STATE EXPENDITURES, FISCAL YEARS 1976-1981 (WOMEN, BUDGET, POPULATION)

The purpose of this study was to analyze the implementation of national family planning policy in the United States, which was embedded in four separate statutes during the period of study, Fiscal Years 1976-81. The design of the study utilized a modification of the Sabatier and Mazmanian framework for policy analysis, which defined implementation as the carrying out of statutory policy. The study was divided into two phases. The first part of the study compared the implementation of family planning policy by each of the pertinent statutes. The second part of the study identified factors that were associated with implementation of federal family planning policy within the context of block grants.^ Implemention was measured here by federal dollars spent for family planning, adjusted for the size of the respective state target populations. Expenditure data were collected from the Alan Guttmacher Institute and from each of the federal agencies having administrative authority for the four pertinent statutes, respectively. Data from the former were used for most of the analysis because they were more complete and more reliable.^ The first phase of the study tested the hypothesis that the coherence of a statute is directly related to effective implementation. Equity in the distribution of funds to the states was used to operationalize effective implementation. To a large extent, the results of the analysis supported the hypothesis. In addition to their theoretical significance, these findings were also significant for policymakers insofar they demonstrated the effectiveness of categorical legislation in implementing desired health policy.^ Given the current and historically intermittent emphasis on more state and less federal decision-making in health and human serives, the second phase of the study focused on state level factors that were associated with expenditures of social service block grant funds for family planning. Using the Sabatier-Mazmanian implementation model as a framework, many factors were tested. Those factors showing the strongest conceptual and statistical relationship to the dependent variable were used to construct a statistical model. Using multivariable regression analysis, this model was applied cross-sectionally to each of the years of the study. The most striking finding here was that the dominant determinants of the state spending varied for each year of the study (Fiscal Years 1976-1981). The significance of these results was that they provided empirical support of current implementation theory, showing that the dominant determinants of implementation vary greatly over time. ^

Longitudinal dyadic data analysis of stroke survivors and their spousal caregivers

Approximately 795,000 new and recurrent strokes occur each year. Because of the resulting functional impairment, stroke survivors are often discharged into the care of a family caregiver, most often their spouse. This dissertation explored the effect that mutuality, a measure of the perceived positive aspects of the caregiving relationship, had on the stress and depression of 159 stroke survivors and their spousal caregivers over the first 12 months post discharge from inpatient rehabilitation. Specifically, cross-lagged regression was utilized to investigate the dyadic, longitudinal relationship between caregiver and stroke survivor mutuality and caregiver and stroke survivor stress over time. Longitudinal meditational analysis was employed to examine the mediating effect of mutuality on the dyads’ perception of family function and caregiver and stroke survivor depression over time.^ Caregivers’ mutuality was found to be associated with their own stress over time but not the stress of the stroke survivor. Caregivers who had higher mutuality scores over the 12 months of the study had lower perceived stress. Additionally, a partner effect of stress for the stroke survivor but not the caregiver was found, indicating that stroke survivors’ stress over time was associated with caregivers’ stress but caregivers’ stress over time was not significantly associated with the stress of the stroke survivor.^ This dissertation did not find mutuality to mediate the relationship between caregivers’ and stroke survivors’ perception of family function at baseline and their own or their partners’ depression at 12 months as hypothesized. However, caregivers who perceived healthier family functioning at baseline and stroke survivors who had higher perceived mutuality at 12 months had lower depression at one year post discharge from inpatient rehabilitation. Additionally, caregiver mutuality at 6 months, but not at baseline or 12 months, was found to be inversely related to caregiver depression at 12 months.^ These findings highlight the interpersonal nature of stress in the context of caregiving, especially among spousal relationships. Thus, health professionals should encourage caregivers and stroke survivors to focus on the positive aspects of the caregiving relationship in order to mitigate stress and depression. ^

Are anatomic brain locations important in determining the clinical outcomes in acute ischemic stroke? --- An exploratory analysis of the NINDS Stroke Trial data

Background and purpose. Brain lesions in acute ischemic stroke measured by imaging tools provide important clinical information for diagnosis and final infarct volume has been considered as a potential surrogate marker for clinical outcomes. Strong correlations have been found between lesion volume and clinical outcomes in the NINDS t-PA Stroke Trial but little has been published about lesion location and clinical outcomes. Studies of the National Institute of Neurological Disorders and Stroke (NINDS) t-PA Stroke Trial data found the direction of the t-PA treatment effect on a decrease in CT lesion volume was consistent with the observed clinical effects at 3 months, but measure of t-PA treatment benefits using CT lesion volumes showed a diminished statistical significance, as compared to using clinical scales. ^ Methods. We used the global test to evaluate the hypothesis that lesion locations were strongly associated with clinical outcomes within each treatment group at 3 months after stroke. The anatomic locations of CT scans were used for analysis. We also assessed the effect of t-PA on lesion location using a global statistical test. ^ Results. In the t-PA group, patients with frontal lesions had larger infarct volumes and worse NIHSS score at 3 months after stroke. The clinical status of patients with frontal lesions in t-PA group was less likely to be affected by lesion volume, as compared to those who had no frontal lesions in at 3 months. For patients within the placebo group, both brain stem and internal capsule locations were significantly associated with a lower odd of having favorable outcomes at 3 months. Using a global test we could not detect a significant effect of t-PA treatment on lesion location although differences between two treatment groups in the proportion of lesion findings in each location were found. ^ Conclusions. Frontal, brain stem, and internal capsule locations were significantly related to clinical status at 3 months after stroke onset. We detect no significant t-PA effect on all 9 locations although proportion of lesion findings in differed among locations between the two treatment groups.^

Pathway analysis of genome-wide association study data in primary biliary cirrhosisa

Genome-wide association studies (GWAS) have successfully identified several genetic loci associated with inherited predisposition to primary biliary cirrhosis (PBC), the most common autoimmune disease of the liver. Pathway-based tests constitute a novel paradigm for GWAS analysis. By evaluating genetic variation across a biological pathway (gene set), these tests have the potential to determine the collective impact of variants with subtle effects that are individually too weak to be detected in traditional single variant GWAS analysis. To identify biological pathways associated with the risk of development of PBC, GWAS of PBC from Italy (449 cases and 940 controls) and Canada (530 cases and 398 controls) were independently analyzed. The linear combination test (LCT), a recently developed pathway-level statistical method was used for this analysis. For additional validation, pathways that were replicated at the P <0.05 level of significance in both GWAS on LCT analysis were also tested for association with PBC in each dataset using two complementary GWAS pathway approaches. The complementary approaches included a modification of the gene set enrichment analysis algorithm (i-GSEA4GWAS) and Fisher's exact test for pathway enrichment ratios. Twenty-five pathways were associated with PBC risk on LCT analysis in the Italian dataset at P<0.05, of which eight had an FDR<0.25. The top pathway in the Italian dataset was the TNF/stress related signaling pathway (p=7.38×10 -4, FDR=0.18). Twenty-six pathways were associated with PBC at the P<0.05 level using the LCT in the Canadian dataset with the regulation and function of ChREBP in liver pathway (p=5.68×10-4, FDR=0.285) emerging as the most significant pathway. Two pathways, phosphatidylinositol signaling system (Italian: p=0.016, FDR=0.436; Canadian: p=0.034, FDR=0.693) and hedgehog signaling (Italian: p=0.044, FDR=0.636; Canadian: p=0.041, FDR=0.693), were replicated at LCT P<0.05 in both datasets. Statistically significant association of both pathways with PBC genetic susceptibility was confirmed in the Italian dataset on i-GSEA4GWAS. Results for the phosphatidylinositol signaling system were also significant in both datasets on applying Fisher's exact test for pathway enrichment ratios. This study identified a combination of known and novel pathway-level associations with PBC risk. If functionally validated, the findings may yield fresh insights into the etiology of this complex autoimmune disease with possible preventive and therapeutic application.^

The relationship between obesity, autoimmune disease, and C-reactive protein: A secondary data analysis of the National Health and Nutrition Examination Survey (NHANES) 2009--2010

Autoimmune diseases are a group of inflammatory conditions in which the body's immune system attacks its own cells. There are over 80 diseases classified as autoimmune disorders, affecting up to 23.5 million Americans. Obesity affects 32.3% of the US adult population, and could also be considered an inflammatory condition, as indicated by the presence of chronic low-grade inflammation. C-reactive protein (CRP) is a marker of inflammation, and is associated with both adiposity and autoimmune inflammation. This study sought to determine the cross-sectional association between obesity and autoimmune diseases in a large, nationally representative population derived from NHANES 2009–10 data, and the role CRP might play in this relationship. Overall, the results determined that individuals with autoimmune disease were 2.11 times more likely to report being overweight than individuals without autoimmune disease and that CRP had a mediating affect on the obesity-autoimmune relationship. ^

A simulation study using the hybrid statistic and the meta-analysis t-test for data with matched and unmatched subjects in the interim analysis of clinical trials

An interim analysis is usually applied in later phase II or phase III trials to find convincing evidence of a significant treatment difference that may lead to trial termination at an earlier point than planned at the beginning. This can result in the saving of patient resources and shortening of drug development and approval time. In addition, ethics and economics are also the reasons to stop a trial earlier. In clinical trials of eyes, ears, knees, arms, kidneys, lungs, and other clustered treatments, data may include distribution-free random variables with matched and unmatched subjects in one study. It is important to properly include both subjects in the interim and the final analyses so that the maximum efficiency of statistical and clinical inferences can be obtained at different stages of the trials. So far, no publication has applied a statistical method for distribution-free data with matched and unmatched subjects in the interim analysis of clinical trials. In this simulation study, the hybrid statistic was used to estimate the empirical powers and the empirical type I errors among the simulated datasets with different sample sizes, different effect sizes, different correlation coefficients for matched pairs, and different data distributions, respectively, in the interim and final analysis with 4 different group sequential methods. Empirical powers and empirical type I errors were also compared to those estimated by using the meta-analysis t-test among the same simulated datasets. Results from this simulation study show that, compared to the meta-analysis t-test commonly used for data with normally distributed observations, the hybrid statistic has a greater power for data observed from normally, log-normally, and multinomially distributed random variables with matched and unmatched subjects and with outliers. Powers rose with the increase in sample size, effect size, and correlation coefficient for the matched pairs. In addition, lower type I errors were observed estimated by using the hybrid statistic, which indicates that this test is also conservative for data with outliers in the interim analysis of clinical trials.^

New methods for quantification and analysis of quantitative real-time polymerase chain reaction data

Quantitative real-time polymerase chain reaction (qPCR) is a sensitive gene quantitation method that has been widely used in the biological and biomedical fields. The currently used methods for PCR data analysis, including the threshold cycle (CT) method, linear and non-linear model fitting methods, all require subtracting background fluorescence. However, the removal of background fluorescence is usually inaccurate, and therefore can distort results. Here, we propose a new method, the taking-difference linear regression method, to overcome this limitation. Briefly, for each two consecutive PCR cycles, we subtracted the fluorescence in the former cycle from that in the later cycle, transforming the n cycle raw data into n-1 cycle data. Then linear regression was applied to the natural logarithm of the transformed data. Finally, amplification efficiencies and the initial DNA molecular numbers were calculated for each PCR run. To evaluate this new method, we compared it in terms of accuracy and precision with the original linear regression method with three background corrections, being the mean of cycles 1-3, the mean of cycles 3-7, and the minimum. Three criteria, including threshold identification, max R2, and max slope, were employed to search for target data points. Considering that PCR data are time series data, we also applied linear mixed models. Collectively, when the threshold identification criterion was applied and when the linear mixed model was adopted, the taking-difference linear regression method was superior as it gave an accurate estimation of initial DNA amount and a reasonable estimation of PCR amplification efficiencies. When the criteria of max R2 and max slope were used, the original linear regression method gave an accurate estimation of initial DNA amount. Overall, the taking-difference linear regression method avoids the error in subtracting an unknown background and thus it is theoretically more accurate and reliable. This method is easy to perform and the taking-difference strategy can be extended to all current methods for qPCR data analysis.^

Analysis of interval -censored events in hypertension studies: Evaluation of treatment of coronary heart disease

Many statistical studies feature data with both exact-time and interval-censored events. While a number of methods currently exist to handle interval-censored events and multivariate exact-time events separately, few techniques exist to deal with their combination. This thesis develops a theoretical framework for analyzing a multivariate endpoint comprised of a single interval-censored event plus an arbitrary number of exact-time events. The approach fuses the exact-time events, modeled using the marginal method of Wei, Lin, and Weissfeld, with a piecewise-exponential interval-censored component. The resulting model incorporates more of the information in the data and also removes some of the biases associated with the exclusion of interval-censored events. A simulation study demonstrates that our approach produces reliable estimates for the model parameters and their variance-covariance matrix. As a real-world data example, we apply this technique to the Systolic Hypertension in the Elderly Program (SHEP) clinical trial, which features three correlated events: clinical non-fatal myocardial infarction, fatal myocardial infarction (two exact-time events), and silent myocardial infarction (one interval-censored event). ^

Integrated Data Sets of the EU FP5 Research Project ORFOIS: Origin and fate of biogenic particle fluxes in the ocean and their interactions with atmospheric CO2 concentrations as well as the marine sediment

For a reliable simulation of the time and space dependent CO2 redistribution between ocean and atmosphere an appropriate time dependent simulation of particle dynamics processes is essential but has not been carried out so far. The major difficulties were the lack of suitable modules for particle dynamics and early diagenesis (in order to close the carbon and nutrient budget) in ocean general circulation models, and the lack of an understanding of biogeochemical processes, such as the partial dissolution of calcareous particles in oversaturated water. The main target of ORFOIS was to fill in this gap in our knowledge and prediction capability infrastructure. This goal has been achieved step by step. At first comprehensive data bases (already existing data) of observations of relevance for the three major types of biogenic particles, organic carbon (POC), calcium carbonate (CaCO3), and biogenic silica (BSi or opal), as well as for refractory particles of terrestrial origin were collated and made publicly available.

(Data S1) Palynological analysis of IODP and ODP sediment cores around the Antarctic margin

The circum-Antarctic Southern Ocean is an important region for global marine food webs and carbon cycling because of sea-ice formation and its unique plankton ecosystem. However, the mechanisms underlying the installation of this distinct ecosystem and the geological timing of its development remain unknown. Here, we show, on the basis of fossil marine dinoflagellate cyst records, that a major restructuring of the Southern Ocean plankton ecosystem occurred abruptly and concomitant with the first major Antarctic glaciation in the earliest Oligocene (~33.6 million years ago). This turnover marks a regime shift in zooplankton-phytoplankton interactions and community structure, which indicates the appearance of eutrophic and seasonally productive environments on the Antarctic margin. We conclude that earliest Oligocene cooling, ice-sheet expansion, and subsequent sea-ice formation were important drivers of biotic evolution in the Southern Ocean.