Kwun Chuen Gary Chan

Regionally-specific diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease

BACKGROUND Diffusion tensor imaging (DTI) studies have shown significant cross-sectional differences among normal controls (NC) mild cognitive impairment (MCI) and Alzheimers disease (AD) patients in several fiber tracts in the brain, but longitudinal assessment is needed. METHODS We studied 75 participants (25 NC, 25 amnestic MCI, and 25 mild AD) at baseline and 3 months later, with both imaging and clinical evaluations. Fractional anisotropy (FA) was analyzed in regions of interest (ROIs) in: (1) fornix, (2) cingulum bundle, (3) splenium, and (4) cerebral peduncles. Clinical data included assessments of clinical severity and cognitive function. Cross-sectional and longitudinal differences in FA, within each ROI, were analyzed with generalized estimating equations (GEE). RESULTS Cross-sectionally, AD patients had lower FA than NC (p<0.05) at baseline and 3 months in the fornix and anterior portion of the cingulum bundle. Compared to MCI, AD cases had lower FA (p<0.05) in these regions and the splenium at 0 and 3 months. Both the fornix and anterior cingulum correlated across all clinical cognitive scores; lower FA in these ROIs corresponded to worse performance. Over the course of 3 months, when the subjects were clinically stable, the ROIs were also largely stable. CONCLUSIONS Using DTI, findings indicate FA is decreased in specific fiber tracts among groups of subjects that vary along the spectrum from normal to AD, and that this measure is stable over short periods of time. The fornix is a predominant outflow tract of the hippocampus and may be an important indicator of AD progression.

Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor

Purpose: Elevated metabolic activity of ovarian cancer cells causes increased ubiquitin-proteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a potentially compensatory histone deacetylase 6 (HDAC6)-dependent lysosomal pathway mediate eukaryotic protein turnover. We hypothesized that up-regulation of the HDAC6-dependent lysosomal pathway occurs in response to UPS stress and proteasomal inhibition, and thus, ovarian cancer cell death can be triggered most effectively by coinhibition of both the proteasome- and HDAC6-dependent protein degradation pathways. Experimental Design: To address this hypothesis, we examined HDAC6 expression patterns in normal and cancerous ovarian tissues and used a novel HDAC6-specific inhibitor, NK84, to address HDAC6 function in ovarian cancer. Results: Abnormally high levels of HDAC6 are expressed by ovarian cancer cells in situ and in culture relative to benign epithelium and immortalized ovarian surface epithelium, respectively. Specific HDAC6 inhibition acts in synergy with the proteasome inhibitor Bortezomib (PS-341) to cause selective apoptotic cell death of ovarian cancer cells at doses that do not cause significant toxicity when used individually. Levels of UPS stress regulate the sensitivity of ovarian cancer cells to proteasome/HDAC6 inhibition. Pharmacologic inhibition of HDAC6 also reduces ovarian cancer cell spreading and migration consistent with its known function in regulating microtubule polymerization via deacetylation of α-tubulin. Conclusion: Our results suggest the elevation of both the proteasomal and alternate HDAC6-dependent proteolytic pathways in ovarian cancer and the potential of combined inhibition of proteasome and HDAC6 as a therapy for ovarian cancer.

Trends in cost and outcomes among adult and pediatric patients with asthma: 2000–2009

BACKGROUND Few studies have examined recent trends in medical expenditures and outcomes in patients with asthma. OBJECTIVE To examine the level and changes in medical expenditures, health status, and functional outcomes in adults, adolescents, and children with asthma and to provide nationally representative estimates of asthma medical costs from 2000 through 2009. METHODS Medical Expenditure Panel Surveys from 2000 through 2009 were used to estimate the trends of medical expenditures (adjusted for medical price inflation), number of workdays lost or schooldays lost, and/or the physical component summary and the mental component summary from the revised 12-Item Short-Form Health Survey, adjusting for sociodemographic variables and comorbidities. RESULTS The averaged physical component summary decreased 0.09 units annually (95% confidence interval 0.02-0.16, P < .01) in adults, but there were no significant changes to the averaged mental component summary. There was no significant change in the number of workdays lost and a marginal decrease of 1.8% per annum in the number of schooldays lost (95% confidence interval -0.1 to 3.5, P = .06). The medical expenditure means increased 2.5% annually in adolescents (95% confidence interval 0.0-4.9, P = .049), but there were no significant changes for adults and children. The total incremental medical expenditures of asthma in the United States were estimated to be

p53 autoantibodies, cytokine levels and ovarian carcinogenesis

62.8 billion in 2009. CONCLUSION This study found that, although medical costs for patients with asthma increased or remained stable across all age groups over a 10-year period, outcomes did not improve. Considering the economic burden of asthma and the previous 10-year performance, continued attention should be focused on asthma management in the United States.

Poor oral health and quality of life in older U.S. adults with diabetes mellitus.

OBJECTIVE To address the hypothesis that type II ovarian carcinoma, mutation of p53 and plasma levels of particular cytokines are associated with the generation of p53-specific serum autoantibody (AAb) responses in patients. METHODS Levels of CA125, 17 cytokines and AAbs to tumor-associated antigens including p53 were measured in plasma of 130 gynecologic tumor patients and 84 healthy controls. TP53 exons 4-9 were sequenced in tumor specimens. RESULTS p53 AAbs are associated with high grade, but not low grade ovarian carcinoma. Seropositivity for p53 AAb occurred only in those ovarian carcinoma patients whose tumors contained mutated TP53, regardless of the exon targeted. Higher p53 AAb levels were detected in ovarian carcinoma patients who had higher stage disease, but p53 AAb levels were not correlated with CA125 levels. Among high-grade carcinoma patients, there was no relationship between p53 AAb seropositivity and seropositivity to other tumor-associated antigens tested, CA125 level or survival outcome. Both high and low grade ovarian carcinoma patients exhibited elevated levels of IL6, IL8 and IL10 as compared to healthy volunteers, although increased levels of IL5, MCP1, MIP1 and TNFalpha were associated only with high grade and advanced disease. Higher levels of p53AAb responses were correlated with elevated circulating IL4 and IL12, but reduced IL8 levels. CONCLUSION Type II, but not type I, ovarian carcinoma patients had elevated serum levels of p53 AAb. P53 AAb is associated with mutation of TP53, higher plasma IL4 and IL12 but lower plasma IL8 levels and no survival advantage.

Oracle, multiple robust and multipurpose calibration in a missing response problem

To determine the association between health‐related quality of life (HRQOL) and oral health in older U.S. adults with diabetes mellitus (DM).

BACKWARD ESTIMATION OF STOCHASTIC PROCESSES WITH FAILURE EVENTS AS TIME ORIGINS

In the presence of a missing response, reweighting the complete case subsample by the inverse of nonmissing probability is both intuitive and easy to implement. When the population totals of some auxiliary variables are known and when the inclusion probabilities are known by design, survey statisticians have developed calibration methods for improving efficiencies of the inverse probability weighting estimators and the methods can be applied to missing data analysis. Model-based calibration has been proposed in the survey sampling literature, where multidimensional auxiliary variables are first summarized into a predictor function from a working regression model. Usually, one working model is being proposed for each parameter of interest and results in different sets of calibration weights for estimating different parameters. This paper considers calibration using multiple working regression models for estimating a single or multiple parameters. Contrary to a common belief that overfitting hurts efficiency, we present three rather unexpected results. First, when the missing probability is correctly specified and multiple working regression models for the conditional mean are posited, calibration enjoys an oracle property: the same semiparametric efficiency bound is attained as if the true outcome model is known in advance. Second, when the missing data mechanism is misspecified, calibration can still be a consistent estimator when any one of the outcome regression models is correctly specified. Third, a common set of calibration weights can be used to improve efficiency in estimating multiple parameters of interest and can simultaneously attain semiparametric efficiency bounds for all parameters of interest. We provide connections of a wide class of calibration estimators, constructed based on generalized empirical likelihood, to many existing estimators in biostatistics, econometrics and survey sampling and perform simulation studies to show that the finite sample properties of calibration estimators conform well with the theoretical results being studied.

Nuisance parameter elimination for proportional likelihood ratio models with nonignorable missingness and random truncation

Stochastic processes often exhibit sudden systematic changes in pattern a short time before certain failure events. Examples include increase in medical costs before death and decrease in CD4 counts before AIDS diagnosis. To study such terminal behavior of stochastic processes, a natural and direct way is to align the processes using failure events as time origins. This paper studies backward stochastic processes counting time backward from failure events, and proposes one-sample nonparametric estimation of the mean of backward processes when follow-up is subject to left truncation and right censoring. We will discuss benefits of including prevalent cohort data to enlarge the identifiable region and large sample properties of the proposed estimator with related extensions. A SEER-Medicare linked data set is used to illustrate the proposed methodologies.

Early Predictors of Lumbar Spine Surgery after Occupational Back Injury: Results from a Prospective Study of Workers in Washington State

We show that the proportional likelihood ratio model proposed recently by Luo & Tsai (2012) enjoys model-invariant properties under certain forms of nonignorable missing mechanisms and randomly double-truncated data, so that target parameters in the population can be estimated consistently from those biased samples. We also construct an alternative estimator for the target parameters by maximizing a pseudo-likelihood that eliminates a functional nuisance parameter in the model. The corresponding estimating equation has a U-statistic structure. As an added advantage of the proposed method, a simple score-type test is developed to test a null hypothesis on the regression coefficients. Simulations show that the proposed estimator has a small-sample efficiency similar to that of the nonparametric likelihood estimator and performs well for certain nonignorable missing data problems.

Food patterns measured by principal component analysis and obesity in the Nepalese adult.

Study Design. Prospective population-based cohort study. Objective. To identify early predictors of lumbar spine surgery within 3 years after occupational back injury. Summary of Background Data. Back injuries are the most prevalent occupational injury in the United States. Few prospective studies have examined early predictors of spine surgery after work-related back injury. Methods. Using Disability Risk Identification Study Cohort (D-RISC) data, we examined the early predictors of lumbar spine surgery within 3 years among Washington State workers, with new workers compensation temporary total disability claims for back injuries. Baseline measures included worker-reported measures obtained approximately 3 weeks after claim submission. We used medical bill data to determine whether participants underwent surgery, covered by the claim, within 3 years. Baseline predictors (P < 0.10) of surgery in bivariate analyses were included in a multivariate logistic regression model predicting lumbar spine surgery. The area under the receiver operating characteristic curve of the model was used to determine the models ability to identify correctly workers who underwent surgery. Results. In the D-RISC sample of 1885 workers, 174 (9.2%) had a lumbar spine surgery within 3 years. Baseline variables associated with surgery (P < 0.05) in the multivariate model included higher Roland-Morris Disability Questionnaire scores, greater injury severity, and surgeon as first provider seen for the injury. Reduced odds of surgery were observed for those younger than 35 years, females, Hispanics, and those whose first provider was a chiropractor. Approximately 42.7% of workers who first saw a surgeon had surgery, in contrast to only 1.5% of those who saw a chiropractor. The area under the receiver operating characteristic curve of the multivariate model was 0.93 (95% confidence interval, 0.92–0.95), indicating excellent ability to discriminate between workers who would versus would not have surgery. Conclusion. Baseline variables in multiple domains predicted lumbar spine surgery. There was a very strong association between surgery and first provider seen for the injury even after adjustment for other important variables.