Knowledge-Guided Bayesian Support Vector Machine Methods For High-Dimensional Data

Support vector machines (SVM) is a popular classification method for analysis of high dimensional data such as genomics data. Recently, new SVM methods have been developed to achieve variable selection through either frequentist regularization or Bayesian shrinkage. The Bayesian framework provides a probabilistic interpretation for SVM and allows direct uncertainty quantification. In this dissertation, we develop four knowledge-guided SVM methods for the analysis of high dimensional data. In Chapter 1, I first review the theory of SVM and existing methods for incorporating the prior knowledge, represented bby graphs into SVM. Second, I review the terminology on variable selection and limitations of the existing methods for SVM variable selection. Last, I introduce some Bayesian variable selection techniques as well as Markov chain Monte Carlo (MCMC) algorithms . In Chapter 2, we develop a new Bayesian SVM method that enables variable selection guided by structural information among predictors, e.g, biological pathways among genes. This method uses a spike and slab prior for feature selection combined with an Ising prior for incorporating structural information. The performance of the proposed method is evaluated in comparison with existing SVM methods in terms of prediction and feature selection in extensive simulations. Furthermore, the proposed method is illustrated in analysis of genomic data from a cancer study, demonstrating its advantage in generating biologically meaningful results and identifying potentially important features. The model developed in Chapter 2 might suffer from the issue of phase transition \citep{li2010bayesian} when the number of variables becomes extremely large. In Chapter 3, we propose another Bayesian SVM method that assigns an adaptive structured shrinkage prior to the coefficients and the graph information is incorporated via the hyper-priors imposed on the precision matrix of the log-transformed shrinkage parameters. This method is shown to outperform the method in Chapter 2 in both simulations and real data analysis.. In Chapter 4, to relax the linearity assumption in chapter 2 and 3, we develop a novel knowledge-guided Bayesian non-linear SVM. The proposed method uses a diagonal matrix with ones representing feature selected and zeros representing feature unselected, and combines with the Ising prior to perform feature selection. The performance of our method is evaluated and compared with several penalized linear SVM and the standard kernel SVM method in terms of prediction and feature selection in extensive simulation settings. Also, analyses of genomic data from a cancer study show that our method yields a more accurate prediction model for patient survival and reveals biologically more meaningful results than the existing methods. In Chapter 5, we extend the work of Chapter 4 and use a joint model to identify the relevant features and learn the structural information among them simultaneously. This model does not require that the structural information among the predictors is known, which is more powerful when the prior knowledge about pathways is limited or inaccurate. We demonstrate that our method outperforms the method developed in Chapter 4 when the prior knowledge is partially true or inaccurate in simulations and illustrate our proposed model with an application to a gliobastoma data set. In Chapter 6, we propose some future works including extending our methods to more general types of outcomes such as categorical or continuous variables

Prevalence of human herpesvirus 8 infection in systemic lupus erythematosus

<p>Abstract</p> <p>Background</p> <p>For decades, scientists have tried to understand the environmental factors involved in the development of systemic lupus erythematosus (SLE), in which viral infections was included. Previous studies have identified Epstein-Barr virus (EBV) to incite SLE. Human herpesvirus 8 (HHV-8), another member of the gammaherpesvirus family, shares a lot in common with EBV. The characteristics of HHV-8 make it a well-suited candidate to trigger SLE.</p> <p>Results</p> <p>In the present study, serum samples from patients (n = 108) with diagnosed SLE and matched controls (n = 122) were collected, and the prevalence of HHV-8 was compared by a virus-specific nested PCR and a whole virus enzyme-linked immunoassay (EIA). There was significant difference in the prevalence of HHV-8 DNA between SLE patients and healthy controls (11 of 107 vs 1 of 122, <it>p </it>= 0.001); significant difference was also found in the detection of HHV-8 antibodies (19 of 107 vs 2 of 122, <it>p </it>< 0.001).</p> <p>We also detected the antibodies to Epstein-Barr virus viral capsid antigen (EBV-VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1). Both patients and controls showed high seroprevalence with no significant difference (106 of 107 vs 119 of 122, <it>p </it>= 0.625).</p> <p>Conclusion</p> <p>Our finding indicated that there might be an association between HHV-8 and the development of SLE.</p

Health-related quality of life after mandibular resection for oral cancer: reconstruction with free fibula flap

Objectives: Mandibular resection for oral cancer is often necessary to achieve an adequate margin of tumor clear - ance. Mandibular resection has been associated with a poor health-related quality of life (HRQOL), particularly before free fibula flap to reconstruct the defect. The aim of this study was to evaluate health-related quality of life in patients who have had mandibular resections of oral cancer and reconstruction with free fibula flap. Study D esigns: There were 115 consecutive patients between 2008 and 2011 who were treated by primary surgery for oral squamous cell carcinoma, 34 patients had a mandibular resection. HRQOL was assessed by means of the 14-item Oral Health Impact Profile (OHIP-14) and University of Washington Quality of Life (UW-QOL) question - naires after 12 months postoperatively. Results: In the UW-QOL the best-scoring domain was mood, whereas the lowest scores were for chewing and saliva. In the OHIP-14 the lowest-scoring domain was social disability, followed by handicap, and psychological disability. Conclusions: Mandible reconstruction with free fibula flap would have significantly influenced on patients' quality of life and oral functions. The socio-cultural data show a fairly low level of education for the majority of patients

Identifying crystal accumulation in granitoids through amphibole composition and in situ zircon O isotopes in North Qilian Orogen

Granitoids are the main constituents of the continental crust, and an understanding of their petrogenesis is key to the origin and evolution of continents. Whether crystal fractionation is the dominant way to generate evolved magmas has long been debated, mostly because such processes would produce large volumes of complementary cumulates, which remains elusive. Mafic magmatic enclaves (MMEs) are ubiquitous in granitoids and their presence was initially recognized as cumulates. However, because many MMEs lack obvious evidence of accumulation, such as the classic cumulate textures and modal layering, the cumulate origin of MMEs has been abandoned and the model of magma mixing between mafic and felsic magmas has become popular. In this study, we conduct a combined study of amphibole composition and in situ O isotopes in zircons on three suites of orogenic granitoids with MMEs from the North Qilian Orogenic Belt (NQOB). We find that the MMEs and their host granodiorites show overlapping zircon δ18O values, affirming that they share the same parental magmas. The amphibole compositions indicate that amphiboles from the MMEs are not in equilibrium with a melt whose composition was that of the bulk-rock. These new data, together with the published bulk-rock data, suggest that the MMEs in our study have clear cumulate signatures and are thus of cumulate origin. Our study provides evidence for crystal accumulation in granitoids in the NQOB. This new understanding calls for re-examination on the petrogenesis of some intermediate magmatic rocks (granitoid/andesite) in discussing models of continental crustal growth

PARP1: Liaison of Chromatin Remodeling and Transcription

Simple Summary: Poly(ADP-ribose) polymerase 1 (PARP1) is perhaps the most studied member of the PARP superfamily and participates in numerous cellular processes. PARP1 inhibitors have been approved as drugs to treat various cancers in clinics, based on its role in DNA repair. Yet, there is a growing body of evidence showing multitasking function of PARP1 in regulation of gene expression. In this review article, we discuss the current knowledge of PARP1 and its conducted enzymatic process, i.e., PARylation, with an emphasis on gene expression by the interaction with transcription factors and regulation of chromatin conformation, dependent or independent of DNA damage. The molecular action mode of PARP1 in gene transcription may present as a potential target for therapeutic intervention of inflammation-related diseases and also for cancer therapy. Abstract Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays a key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, synthesizes long and branched polymers of ADP-ribose (PAR) onto acceptor proteins, thereby modulating their function and their local surrounding. PARP1 is the most prominent of the PARPs and is responsible for the production of about 90% of PAR in the cell. Therefore, PARP1 and PARylation play a pleotropic role in a wide range of cellular processes, such as DNA repair and genomic stability, cell death, chromatin remodeling, inflammatory response and gene transcription. PARP1 has DNA-binding and catalytic activities that are important for DNA repair, yet also modulate chromatin conformation and gene transcription, which can be independent of DNA damage response. PARP1 and PARylation homeostasis have also been implicated in multiple diseases, including inflammation, stroke, diabetes and cancer. Studies of the molecular action and biological function of PARP1 and PARylation provide a basis for the development of pharmaceutic strategies for clinical applications. This review focuses primarily on the role of PARP1 in the regulation of chromatin remodeling and transcriptional activation

COVID-19 and bilingual children’s home language environment: Digital media, socioeconomic status, and language status

Input is considered crucial in bilingual children’s language development. This is especially true for bilingual children’s mother tongue language learning given its common reduction in input opportunities due to the dominance of one language within society, as seen in countries and regions from Wales to Singapore. Previous studies tend to focus on the quantity and quality of conventional active communication and resources (e.g., speaking and reading with parents) on bilingual children’s language development, and substantially, fewer studies have explored this topic from the perspective of digital media. However, the COVID-19 pandemic has accentuated the critical role of digital media in various aspects of life, including bilingual children’s home language environment. Thus, to holistically understand bilingual children’s daily language input patterns, it is imperative to explore both their conventional and digital media input resources. The current study focuses on English-Mandarin bilingual children in Singapore and would like to explore (1) whether their conventional and digital media language environments have been affected by the COVID-19 pandemic and (2) whether the societal status of a language and familial socioeconomic status (SES) would affect bilingual children’s conventional and digital media input. Survey data from 162 parents of English-Mandarin bilingual preschoolers (3 to 6 years old) were used to explore the two research questions. Two online parental questionnaires were employed for data collection. One-way repeated-measures MANOVA and path models were used to address the questions. The results indicated that input patterns from nuclear family members had not been affected by COVID-19; however, the amount and frequency of conventional and digital media materials and activities increased significantly since COVID-19. Higher-SES families possessed more conventional materials and conducted conventional activities more often, while lower-SES families possessed more digital media materials. Both conventional and digital media materials and activities were richer in English than in Mandarin. Higher-SES families perceived digital media usage for learning to be of less importance than lower-SES families. The implications for early bilingual learning following COVID-19 are discussed

The Central Domain of MCPH1 Controls Development of the Cerebral Cortex and Gonads in Mice

MCPH1 is the first gene identified to be responsible for the human autosomal recessive disorder primary microcephaly (MCPH). Mutations in the N-terminal and central domains of MCPH1 are strongly associated with microcephaly in human patients. A recent study showed that the central domain of MCPH1, which is mainly encoded by exon 8, interacts with E3 ligase βTrCP2 and regulates the G2/M transition of the cell cycle. In order to investigate the biological functions of MCPH1’s central domain, we constructed a mouse model that lacked the central domain of MCPH1 by deleting its exon 8 (designated as Mcph1 -Δe8). Mcph1 -Δe8 mice exhibited a reduced brain size and thinner cortex, likely caused by a compromised self-renewal capacity and premature differentiation of Mcph1 -Δe8 neuroprogenitors during corticogenesis. Furthermore, Mcph1 -Δe8 mice were sterile because of a loss of germ cells in the testis and ovary. The embryonic fibroblasts of Mcph1 -Δe8 mice exhibited premature chromosome condensation (PCC). All of these findings indicate that Mcph1 -Δe8 mice are reminiscent of MCPH1 complete knockout mice and Mcph1 -ΔBR1 mice. Our study demonstrates that the central domain of MCPH1 represses microcephaly, and is essential for gonad development in mammals

Adiponectin improves coronary no-reflow injury by protecting the endothelium in rats with type 2 diabetes mellitus.

To determine the effect of adiponectin (APN) on the coronary no-reflow (NR) injury in rats with Type 2 diabetes mellitus (T2DM), 80 male Sprague-Dawley rats were fed with a high-sugar-high-fat diet to build a T2DM model. Rats received vehicle or APN in the last week and then were subjected to myocardial ischemia reperfusion (MI/R) injury. Endothelium-dependent vasorelaxation of the thoracic aorta was significantly decreased and serum levels of endothelin-1 (ET-1), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were noticably increased in T2DM rats compared with rats without T2DM. Serum APN was positively correlated with the endothelium-dependent vasorelaxation, but negatively correlated with the serum level of ET-1. Treatment with APN improved T2DM-induced endothelium-dependent vasorelaxation, recovered cardiac function, and decreased both NR size and the levels of ET-1, ICAM-1 and VCAM-1. Hypoadiponectinemia was associated with the aggravation of coronary NR in T2DM rats. APN could alleviate coronary NR injury in T2DM rats by protecting the endothelium and improving microcirculation

Autoantibodies against the Catalytic Domain of BRAF Are Not Specific Serum Markers for Rheumatoid Arthritis

BACKGROUND: Autoantibodies to the catalytic domain of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) have been recently identified as a new family of autoantibodies involved in rheumatoid arthritis (RA). The objective of this study was to determine antibody responses to the catalytic domain of BRAF in RA and other autoimmune diseases. The association between RA-related clinical indices and these antibodies was also assessed. METHODOLOGY/PRINCIPAL FINDINGS: The presence of autoantibodies to the catalytic domain of BRAF (anti-BRAF) or to peptide P25 (amino acids 656-675 of the catalytic domain of BRAF; anti-P25) was determined in serum samples from patients with RA, primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), and healthy controls by using indirect enzyme-linked immunosorbent assays (ELISAs) based on the recombinant catalytic domain of BRAF or a synthesized peptide, respectively. Associations of anti-BRAF or anti-P25 with disease variables of RA patients were also evaluated. Our results show that the BRAF-specific antibodies anti-BRAF and anti-P25 are equally present in RA, pSS, and SLE patients. However, the erythrocyte sedimentation rate (ESR) used to detect inflammation was significantly different between patients with and without BRAF-specific antibodies. The anti-BRAF-positive patients were found to have prolonged disease, and active disease occurred more frequently in anti-P25-positive patients than in anti-P25-negative patients. A weak but significant correlation between anti-P25 levels and ESRs was observed (r = 0.319, p = 0.004). CONCLUSIONS/SIGNIFICANCE: The antibody response against the catalytic domain of BRAF is not specific for RA, but the higher titers of BRAF-specific antibodies may be associated with increased inflammation in RA

Invisible Backdoor Attack with Dynamic Triggers against Person Re-identification

In recent years, person Re-identification (ReID) has rapidly progressed with wide real-world applications, but also poses significant risks of adversarial attacks. In this paper, we focus on the backdoor attack on deep ReID models. Existing backdoor attack methods follow an all-to-one/all attack scenario, where all the target classes in the test set have already been seen in the training set. However, ReID is a much more complex fine-grained open-set recognition problem, where the identities in the test set are not contained in the training set. Thus, previous backdoor attack methods for classification are not applicable for ReID. To ameliorate this issue, we propose a novel backdoor attack on deep ReID under a new all-to-unknown scenario, called Dynamic Triggers Invisible Backdoor Attack (DT-IBA). Instead of learning fixed triggers for the target classes from the training set, DT-IBA can dynamically generate new triggers for any unknown identities. Specifically, an identity hashing network is proposed to first extract target identity information from a reference image, which is then injected into the benign images by image steganography. We extensively validate the effectiveness and stealthiness of the proposed attack on benchmark datasets, and evaluate the effectiveness of several defense methods against our attack