Statistical Learning Methods for High-dimensional Classification and Regression

With the recent advancement of technology, large and heterogeneous data containing enormous variables of mixed types have become increasingly popular, great challenges in computation and theory have arisen for classical methods in classification and regression. It is of great interest to develop new statistical methods that are computationally efficient and theoretically sound for classification and regression using high-dimensinoal and heterogeneous data. In this dissertation, we specifically address the problems in the computation of high-dimensional linear discriminant analysis, and in high-dimensional linear regression and ordinal classification with mixed covariates. First, we propose an efficient greedy search algorithm that depends solely on closed-form formulae to learn a high-dimensional linear discriminant analysis (LDA) rule. We establish theoretical guarantee of its statistical properties in terms of variable selection and error rate consistency; in addition, we provide an explicit interpretation of the extra information brought by an additional feature in a LDA problem under some mild distributional assumptions. We demonstrate that this new algorithm drastically improves computational speed compared with other high-dimensional LDA methods, while maintaining comparable or even better classification performance through extensive simulation studies and real data analysis. Second, we propose a semiparametric Latent Mixed Gaussian Copula Regression (LMGCR) model to perform linear regression for high-dimensional mixed data. The model assumes that the observed mixed covariates are generated from latent variables that follow the Gaussian copula. We develop an estimator of the regression coefficients in LMGCR and prove its estimation and variable selection consistency. In addition, we devise a prediction rule given by LMGCR and quantify its prediction error under mild conditions. We demonstrate that the proposed model has superior performance in both coefficient estimation and prediction through extensive simulation studies and real data analysis. Finally, we propose a semiparametric Latent Mixed Gaussian Copula Classification (LMGCC)rule to perform classification of ordinal response using unnormalized high-dimensional data. Our clas- sification rule learns the Bayes rule derived from joint modeling of ordinal response and continuous features through a latent Gaussian copula model. We develop an estimator of the regression coeffi- cients in predicting the latent response and prove its estimation and variable selection consistency. In addition, we establish that our devised LMGCC has error rate consistency. We demonstrate that the proposed method has superior performance in ordinal classification through extensive simulation studies and real data analysis.Doctor of Philosoph

Amino acid intakes are associated with bone mineral density and prevalence of low bone mass in women: evidence from discordant monozygotic twins

Although a higher protein intake, particularly from vegetable sources, has been shown to be associated with higher bone mineral density (BMD) the relative impact of specific amino acids (AA) on BMD and risk of osteoporosis remains to be determined. Mechanistic research suggests that a number of specific AA, including five non-essential AA, alanine, arginine, glutamic acid, glycine and proline, may play a role in bone health, principally through improved production of insulin and insulin-like growth factor 1 and the synthesis of collagen and muscle protein. However to date, no previous studies have examined the associations between habitual intake of AA and direct measures of BMD and prevalence of osteoporosis or osteopenia and no studies have examined this relationship in discordant identical twin-pairs. In these analyses of female monozygotic twin-pairs discordant for AA intake (n=135), twins with higher intakes of alanine and glycine had significantly higher BMD at the spine than their co-twins with within-pair differences in spine-BMD of 0.012 g/cm2 (SE 0.01 P=0.039) and 0.014g/cm2 (SE 0.01 P=0.026) respectively. Furthermore, in cross-sectional multivariable analyses of 3160 females aged 18-79y, a higher intake of total protein was significantly associated with higher DXA-measured BMD at the spine (Q4-Q1 0.017g/cm2 SE 0.01 P=0.035) and forearm (Q4-Q1 0.010g/cm2 SE 0.003 P=0.002). Intake of six AA (alanine, arginine, glutamic acid, leucine, lysine and proline) were associated with higher BMD at the spine and forearm with the strongest association observed for leucine (Q4-Q1 0.024g/cm2 SE 0.01 P=0.007). When intakes were stratified by protein source, vegetable or animal, prevalence of osteoporosis or osteopenia was 13-19% lower comparing extreme quartiles of vegetable intake for five AA (not glutamic acid or proline). These data provide evidence to suggest that intake of protein and several AA, including alanine and glycine, may be beneficial for bone health, independent of genetic background

Role of Ca2+ and L-Phe in Regulating Functional Cooperativity of Disease- Associated ‘‘Toggle’’ Calcium-Sensing Receptor Mutations

The Ca2+-sensing receptor (CaSR) regulates Ca2+ homeostasis in the body by monitoring extracellular levels of Ca2+ ([Ca2+]o) and amino acids. Mutations at the hinge region of the N-terminal Venus flytrap domain (VFTD) produce either receptor inactivation (L173P, P221Q) or activation (L173F, P221L) related to hypercalcemic or hypocalcemic disorders. In this paper, we report that both L173P and P221Q markedly impair the functional positive cooperativity of the CaSR as reflected by [Ca2+]o–induced [Ca2+]i oscillations, inositol-1-phosphate (IP1) accumulation and extracellular signal-regulated kinases (ERK1/2) activity. In contrast, L173F and P221L show enhanced responsiveness of these three functional readouts to [Ca2+]o. Further analysis of the dynamics of the VFTD mutants using computational simulation studies supports disruption in the correlated motions in the loss-offunction CaSR mutants, while these motions are enhanced in the gain-of-function mutants. Wild type (WT) CaSR was modulated by L-Phe in a heterotropic positive cooperative way, achieving an EC50 similar to those of the two activating mutations. The response of the inactivating P221Q mutant to [Ca2+]o was partially rescued by L-Phe, illustrating the capacity of the L-Phe binding site to enhance the positive homotropic cooperativity of CaSR. L-Phe had no effect on the other inactivating mutant. Moreover, our results carried out both in silico and in intact cells indicate that residue Leu173, which is close to residues that are part of the L-Phe-binding pocket, exhibited impaired heterotropic cooperativity in the presence of L-Phe. Thus, Pro221 and Leu173 are important for the positive homo- and heterotropic cooperative regulation elicited by agonist binding

N-Benzoimidazole/Oxadiazole Hybrid Universal Electron Acceptors for Highly Efficient Exciplex-Type Thermally Activated Delayed Fluorescence OLEDs

Recently, donor/acceptor type exciplex have attracted considerable interests due to the low driving voltages and small singlet-triplet bandgaps for efficient reverse intersystem crossing to achieve 100% excitons for high efficiency thermally activated delayed fluorescence (TADF) OLEDs. Herein, two N-linked benzoimidazole/oxadiazole hybrid electron acceptors were designed and synthesized through simple catalyst-free C-N coupling reaction. 24iPBIOXD and iTPBIOXD exhibited deep-blue emission with peak at 421 and 459 nm in solution, 397 and 419 nm at film state, respectively. The HOMO/LUMO energy levels were −6.14/−2.80 for 24iPBIOXD and −6.17/−2.95 eV for iTPBIOXD. Both compounds could form exciplex with conventional electron donors such as TAPC, TCTA, and mCP. It is found that the electroluminescent performance for exciplex-type OLEDs as well as the delayed lifetime was dependent with the driving force of both HOMO and LUMO energy offsets on exciplex formation. The delayed lifetime from 579 to 2,045 ns was achieved at driving forces close to or larger than 1 eV. Two TAPC based devices possessing large HOMO/LUMO offsets of 1.09–1.34 eV exhibited the best EL performance, with maximum external quantum efficiency (EQE) of 9.3% for 24iPBIOXD and 7.0% for iTPBIOXD acceptor. The TCTA containing exciplex demonstrated moderate energy offsets (0.88–1.03 eV) and EL efficiency (~4%), while mCP systems showed the poorest EL performance (EQE <1%) and shortest delayed lifetime of <100 ns due to inadequate driving force of 0.47–0.75 eV for efficient exciplex formation

Caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury is mediated via RhoA and ROCK activation in major pelvic ganglion

Axonal injury due to prostatectomy leads to Wallerian degeneration of the cavernous nerve (CN) and erectile dysfunction (ED). Return of potency is dependent on axonal regeneration and reinnervation of the penis. Following CN injury (CNI), RhoA and Rho-associated protein kinase (ROCK) increase in penile endothelial and smooth muscle cells. Previous studies indicate that nerve regeneration is hampered by activation of RhoA/ROCK pathway. We evaluated the role of RhoA/ROCK pathway in CN regulation following CNI using a validated rat model. CNI upregulated gene and protein expression of RhoA/ROCK and caspase-3 mediated apoptosis in the major pelvic ganglion (MPG). ROCK inhibitor (ROCK-I) prevented upregulation of RhoA/ROCK pathway as well as activation of caspase-3 in the MPG. Following CNI, there was decrease in the dimer to monomer ratio of neuronal nitric oxide synthase (nNOS) protein and lowered NOS activity in the MPG, which were prevented by ROCK-I. CNI lowered intracavernous pressure and impaired non-adrenergic non-cholinergic-mediated relaxation in the penis, consistent with ED. ROCK-I maintained the intracavernous pressure and non-adrenergic non-cholinergic-mediated relaxation in the penis following CNI. These results suggest that activation of RhoA/ROCK pathway mediates caspase-3 dependent apoptosis of nitrergic neurons in the MPG following CNI and that ROCK-I can prevent post-prostatectomy ED