Nonparametric MANOVA Approaches for Non-Normal Multivariate Outcomes

Comparisons between groups play a central role in clinical research. As these comparisons often entail many potentially correlated response variables, the classical multivariate general linear model has been accepted as a standard tool. However, parametric methods require distributional assumptions such as multivariate normality while non-normal data often exist in clinical research. For example, a clinical trial investigating a treatment for depression is designed as a longitudinal study and the main outcome is survey scores of subjects on several time points, while the scores are ordinal. Although non-parametric multivariate methods are available in the statistical literature, they are not seen to be commonly used in clinical research. Moreover, automatic deletion of cases with missing values in response variables is a shortcoming of standard software when performing multivariate tests. This dissertation addresses the issues of violation of multivariate normality assumption and missing data, focusing on the non-parametric multivariate Kruskal-Wallis (MKW) test, likelihood-based and permutation-based methods. First, an R-based program is written to compute the p-value of MKW test for group comparison. Simulation studies show that the permutation-based MKW test provides better coverage and higher power level than likelihood-based MKW test and classical MANOVA. Second, an extension of MKW test is proposed for multivariate data with missingness. The proposed method retrieves information in partially observed cases and is permutation-based. A sensitivity analysis compares the performance of the proposed extension and the standard test utilizing only complete cases. Results show that the proposed extended method provides higher power level, encompassing a broad spectrum of multivariate effect sizes. An illustrative example using data from a psychiatric clinical trial is provided. The R program is ready to use for applied statistician. The public health relevance of this work lies in the development of a new powerful methodology with user-friendly computer software for group comparisons in non-normal multivariate data with or without missingness

Up-regulation of the human-specific CHRFAM7A gene protects against renal fibrosis in mice with obstructive nephropathy

Renal fibrosis is a major factor in the progression of chronic kidney diseases. Obstructive nephropathy is a common cause of renal fibrosis, which is also accompanied by inflammation. To explore the effect of human-specific CHRFAM7A expression, an inflammation-related gene, on renal fibrosis during obstructive nephropathy, we studied CHRFAM7A transgenic mice and wild type mice that underwent unilateral ureteral obstruction (UUO) injury. Transgenic overexpression of CHRFAM7A gene inhibited UUO-induced renal fibrosis, which was demonstrated by decreased fibrotic gene expression and collagen deposition. Furthermore, kidneys from transgenic mice had reduced TGF-β1 and Smad2/3 expression following UUO compared with those from wild type mice with UUO. In addition, the overexpression of CHRFAM7A decreased release of inflammatory cytokines in the kidneys of UUO-injured mice. In vitro, the overexpression of CHRFAM7A inhibited TGF-β1-induced increase in expression of fibrosis-related genes in human renal tubular epithelial cells (HK-2 cells). Additionally, up-regulated expression of CHRFAM7A in HK-2 cells decreased TGF-β1-induced epithelial-mesenchymal transition (EMT) and inhibited activation f TGF-β1/Smad2/3 signalling pathways. Collectively, our findings demonstrate that overexpression of the human-specific CHRFAM7A gene can reduce UUO-induced renal fibrosis by inhibiting TGF-β1/Smad2/3 signalling pathway to reduce inflammatory reactions and EMT of renal tubular epithelial cells

Optimism, response to treatment of depression, and rehospitalization after coronary artery bypass graft surgery.

<p>OBJECTIVE: Optimism has been associated with a lower risk of rehospitalization after coronary artery bypass graft (CABG) surgery, but little is known about how optimism affects treatment of depression in post-CABG patients.</p> <p>METHODS: Using data from a collaborative care intervention trial for post-CABG depression, we conducted exploratory post hoc analyses of 284 depressed post-CABG patients (2-week posthospitalization score in the 9-item Patient Health Questionnaire ≥ 10) and 146 controls without depression who completed the Life Orientation Test - Revised (full scale and subscale) to assess dispositional optimism. We classified patients as optimists and pessimists based on the sample-specific Life Orientation Test - Revised distributions in each cohort (full sample, depressed, nondepressed). For 8 months, we assessed health-related quality of life (using the 36-item Short-Form Health Survey) and mood symptoms (using the Hamilton Rating Scale for Depression [HRS-D]) and adjudicated all-cause rehospitalization. We defined treatment response as a 50% or higher decline in HRS-D score from baseline.</p> <p>RESULTS: Compared with pessimists, optimists had lower baseline mean HRS-D scores (8 versus 15, p = .001). Among depressed patients, optimists were more likely to respond to treatment at 8 months (58% versus 27%, odds ratio = 3.02, 95% confidence interval = 1.28-7.13, p = .01), a finding that was not sustained in the intervention group. The optimism subscale, but not the pessimism subscale, predicted treatment response. By 8 months, optimists were less likely to be rehospitalized (odds ratio = 0.54, 95% confidence interval = 0.32-0.93, p = .03).</p> <p>CONCLUSIONS: Among depressed post-CABG patients, optimists responded to depression treatment at higher rates. Independent of depression, optimists were less likely to be rehospitalized by 8 months after CABG. Further research should explore the impact of optimism on these and other important long-term post-CABG outcomes.</p

Current Perspectives of Neuroendocrine Regulation in Liver Fibrosis

Liver fibrosis is a complicated process that involves different cell types and pathological factors. The excessive accumulation of extracellular matrix (ECM) and the formation of fibrotic scar disrupt the tissue homeostasis of the liver, eventually leading to cirrhosis and even liver failure. Myofibroblasts derived from hepatic stellate cells (HSCs) contribute to the development of liver fibrosis by producing ECM in the area of injuries. It has been reported that the secretion of the neuroendocrine hormone in chronic liver injury is different from a healthy liver. Activated HSCs and cholangiocytes express specific receptors in response to these neuropeptides released from the neuroendocrine system and other neuroendocrine cells. Neuroendocrine hormones and their receptors form a complicated network that regulates hepatic inflammation, which controls the progression of liver fibrosis. This review summarizes neuroendocrine regulation in liver fibrosis from three aspects. The first part describes the mechanisms of liver fibrosis. The second part presents the neuroendocrine sources and neuroendocrine compartments in the liver. The third section discusses the effects of various neuroendocrine factors, such as substance P (SP), melatonin, as well as &alpha;-calcitonin gene-related peptide (&alpha;-CGRP), on liver fibrosis and the potential therapeutic interventions for liver fibrosis