STATISTICAL METHODS FOR JOINT ANALYSIS OF MULTIPLE PHENOTYPES AND THEIR APPLICATIONS FOR PHEWAS

Genome-wide association studies (GWAS) have successfully detected tens of thousands of robust SNP-trait associations. Earlier researches have primarily focused on association studies of genetic variants and some well-defined functions or phenotypic traits. Emerging evidence suggests that pleiotropy, the phenomenon of one genetic variant affects multiple phenotypes, is widespread, especially in complex human diseases. Therefore, individual phenotype analyses may lose statistical power to identify the underlying genetic mechanism. Contrasting with single phenotype analyses, joint analysis of multiple phenotypes exploits the correlations between phenotypes and aggregates multiple weak marginal effects and is therefore likely to provide new insights into the functional consequences of genetic variations. This dissertation includes two papers, corresponding to two primary research projects I have done during my Ph.D. study, with each distributed in one chapter. Chapter 1 proposed an innovative method, which referred to as HC-CLC, for joint analysis of multipole phenotypes using a Hierarchical Clustering (HC) approach followed by a Clustering Linear Combination (CLC) method. The HC step partitions phenotypes into clusters. The CLC method is then used to test the association between the genetic variant and all phenotypes, which is done by combining individual test statistics while taking full advantage of the clustering information in the HC step. Extensive simulations together with the COPDGene data analysis have been used to assess the Type I error rates and the power of our proposed method. Our simulation results demonstrate that the Type I error rates of HC-CLC are effectively controlled in different realistic settings. HC-CLC either outperforms all other methods or has statistical power that is very close to the most powerful alternative method with which it has been compared. In addition, our real data analysis shows that HC-CLC is an appropriate method for GWAS. Chapter 2 redesigned the PheCLC (Phenome-wide association study that uses the CLC method) which was previously developed by our research group. The refined method is then applied on the UKBiobank data, a large cohort study across the United Kingdom, to test the validity and understand the limitations of the proposed method. We have named our new method UKB-PheCLC. The UKB-PheCLC method is an EHR-based PheWAS. In the first step, it classifies the whole phenome into different phenotypic categories according to the UK Biobank ICD codes. In the second step, the CLC method is applied to each phenotypic category to derive a CLC-based p-value for testing the association between the genetic variant of interest and all phenotypes in that category. In the third step, the CLC-based p-values of all categories are combined by using a strategy resemble that of the Adaptive Fisher\u27s Combination (AFC) method. Overall, UKB-PheCLC harnesses the powerful resource of the UK Biobank and considers the possibility that phenotypes can be grouped into different phenotypic categories, which is very common in EHR-based PheWAS. Moreover, UKB-PheCLC can handle both qualitative and quantitative phenotypes, and it also doesn’t require raw phenotype information. The real data analysis results confirm that UKB-PheCLC is more powerful than the existing methods we have it compared with. Thus, UKB-PheCLC can serve as a compelling method for phenome-wide association study

Vulnerability assessment and adaptation of dryland agriculture on the Chinese Loess Plateau and Australian Wheatbelt

University of Technology Sydney. Faculty of Science.Sustainable agricultural production on drylands faces challenges from increasing food demand and climate change. The interrelated issues of production instability, vulnerability to climate change and the need for effective adaptations require a comprehensive and integrated ecological-economic assessment. Accordingly, this thesis examines two key dryland agricultural regions, the Australian Wheatbelt and the Chinese Loess Plateau, to provide new insights and improved approaches for dryland agricultural management. Decomposition analysis was undertaken to identify the driving forces in growth and instability of Australian wheat production from 1900-2010. Results show that instability of Australian wheat production has not been reduced significantly in the past century. The increasing trend of wheat production was mainly due to sowing area increases whilst the yearly fluctuation of production is mainly caused by variable yields. A focus on yield alone may therefore bias assessments of the vulnerability of agriculture to climate change. A conceptual framework was developed to assess the agricultural vulnerability of 243 rural counties on the Chinese Loess Plateau. A vulnerability index for each county was calculated from statistical indicators. Within the 49 most vulnerable counties, 42 were characterised by high exposure and sensitivity but low adaptive capacity. The most vulnerable area was found to be located in the central northeast-southwest belt of Loess Plateau. Upon identifying vulnerable areas, the effectiveness of the regionally significant adaptation, plastic film mulching, on maize growth was assessed in the Loess Plateau. The APSIM model was calibrated and validated using field experiment data, then applied to simulate maize growth during 1961-2010 at Changwu station. Plastic film mulching could significantly increase maize yields by an average of 15.3%, and increase the cumulative probability at mid-range yield levels at Changwu. The advantage was found to be more pronounced in dry years than wet years. Geostatistical analysis was used to extend the modelling across the Loess Plateau to identify areas with climate favourable for adopting plastic film mulching. The central south presented high and stable production while the northwest showed the greatest potential in yield increase and variability reduction. The multiscale studies concern both developing and developed counties, can be referenced to location-specific information for policy makers and researchers. The principles, frameworks, technologies and tools can be modified and adopted in other dryland regions

Effects of different disc locations on oil-film instability in a rotor system

Taking a rotor-bearing system attached with two discs as a research object, the effect of axial locations of two discs on the oil-film instability is investigated under out-of-phase unbalance of two discs. The nonlinear dynamic behavior of the rotor bearing system is analyzed by applying a finite element method (FEM). The left and right sliding bearings are simulated by an unsteady nonlinear oil-film force model based on the assumption of short bearings, respectively. The paper mainly focuses on the second oil-film instability law with two changing methods of disc locations and the complicated nonlinear responses of the rotor system are also analyzed through the amplitude-frequency response of oil-film force from the right bearing, spectrum cascades diagram. The results show that the phenomena of the first and second mode oil-film instabilities have more to do with the natural frequencies and the characteristics of oil-film force of the left or right bearing. When the second natural frequency is lower and the right disc is close to the oil-film bearing, the oil-film force will become larger, which will cause oil-film instability violently. The results have an important significance for the fault diagnosis of oil-film instability and structural design of bearing-rotor system with this type

Correlation between resistance of eggplant and defense-related enzymes and biochemical substances of leaves

14 eggplant cultivars were inoculated by Verticillium dahliae to screen their resistance against verticillium wilt. The resistances were shown as the disease incidence and disease index, and eggplant cultivars were classified into resistant type (R), moderate resistant type (MR), tolerant type (T), moderate susceptible (MS) and susceptible type (S), according to the final disease index. To find out the correlated physiological and biochemical indexes for evaluating the resistance of eggplant to verticillium wilt, the activities of defense-related enzymes, and the contents of some biochemical substances of leaves were investigated. The results show that the activities of polyphenol oxidase (PPO) and phenylalanine ammonia lyase (PAL) were significantly positively correlated with resistance (P <0.01) and the resistance was significantly positively correlated with the activity of peroxidase (POD) and the content of total chlorophyll (P<0.05), but significantly negatively correlated with the relative electric conductivity and the content of malondialdehyde (MDA) (P<0.05). The correlations between resistance and catalase (CAT) activity, the contents of sucrose, soluble protein and proline, were not detected.Keywords: Verticillium wilt, eggplant, disease resistance, defense-related enzyme, biochemical substanc

High serum mannose in colorectal cancer: a novel biomarker of lymph node metastasis and poor prognosis

BackgroundLymph node status is an important prognostic indicator and it significantly influences treatment decisions for colorectal cancer (CRC). The objective of this study was to evaluate the ability of serum monosaccharides in predicting lymph node metastasis (LNM) and prognosis.MethodsHigh performance anion exchange chromatography coupled with pulsed amperometric detector (HPAEC-PAD) was used to quantify serum monosaccharides from 252 CRC patients. Receiver operating characteristic (ROC) curves were used to evaluate predictive performance of parameters. Predictors of LNM were evaluated by univariate and multivariate analyses. The prognostic role of the factors was evaluated by survival analysis.ResultsThe levels of serum mannose (Man) and galactose (Gal) were significantly increased in patients with LNM (p <0.0001, p =0.0017, respectively). The area under the curves (AUCs) of Man was 0.8140, which was higher than carcinoembryonic antigen (CEA) (AUC =0.6523). Univariate and multivariate analyses demonstrated histologic grade (G3) (odds ratio [OR] =2.60, p =0.043), histologic grade (mucin-producing subtype) (odds ratio [OR] =3.38, p =0.032), lymphovascular invasion (LVI) (OR =2.42, p <0.01), CEA (>5ng/ml) (OR =1.85, p =0.042) and high Man (OR =2.65, p =0.006) to be independent risk factors of LNM. The survival analysis showed that the high serum Man was independent risk factor for poor prognosis in CRC patients (HR=1.75, p =0.004).ConclusionsThe Man is superior to CEA in prediction of LNM for CRC patients. Man is expected to be a predictor for LNM in CRC. High serum Man is associated with poor prognosis of CRC patients

Accumulation of cinnamic acid and vanillin in eggplant root exudates and the relationship with continuous cropping obstacle

The contents of cinnamic acid and vanillin in eggplant root exudates and soil were determined by HPLC. The results showed that cinnamic acid and vanillin might remain in soil after the root of eggplant is released. With the extending growth stage and planting year of eggplant, the contents in root exudates, rhizosphere and continuous cropping soil increased. In bioassay and field studies, the allelopathy of cinnamic acid and vanillin to the verticillium wilt (V. dahliae) and the eggplant was observed, and when the concentration of cinnamic acid or vanillin was at 1 and 4mmol ⇦ -1, it inhibited the eggplant growth, while the occurrence of verticillium wilt was promoted. A high concentration of cinnamic acid and vanillin caused eggplant autotoxicity and increased the risk of disease infection, which finally led to continuous cropping obstacle.Keywords: Cinnamic acid, vanillin, root exudates, soil, verticillium wilt, continuous cropping obstacl

Design of Thermal Barrier Coatings Thickness for Gas Turbine Blade Based on Finite Element Analysis

Thermal barrier coatings (TBCs) are deposited on the turbine blade to reduce the temperature of underlying substrate, as well as providing protection against the oxidation and hot corrosion from high temperature gas. Optimal ceramic top-coat thickness distribution on the blade can improve the performance and efficiency of the coatings. Design of the coatings thickness is a multiobjective optimization problem due to the conflicts among objectives of high thermal insulation performance, long operation durability, and low fabrication cost. This work developed a procedure for designing the TBCs thickness distribution for the gas turbine blade. Three-dimensional finite element models were built and analyzed, and weighted-sum approach was employed to solve the multiobjective optimization problem herein. Suitable multiregion top-coat thickness distribution scheme was designed with the considerations of manufacturing accuracy, productivity, and fabrication cost

Word Familiarity Modulated the Effects of Category Familiarity on Memory Performance

Previous studies have shown that prior knowledge can have both enhancing and detrimental effects on memory for relevant information. Few studies have explored the boundary conditions under which prior knowledge facilitates or interferes with memory processes. In addition, to what extent the effects of prior knowledge change over time is unclear. In this study, we addressed this question by separating category familiarity (i.e., prior conceptual knowledge) and stimulus familiarity at different retention intervals. Participants were tested with a recognition task after they learned four types of words, that is., familiar words from familiar categories (FwordFcate) and unfamiliar categories (FwordUcate) as well as unfamiliar words from familiar (UwordFcate) and unfamiliar categories (UwordUcate). The results showed a significant interaction between category familiarity and word familiarity, that is, unfamiliar words, but not familiar words, from familiar categories were remembered better than those from unfamiliar categories. The enhancing effect of category familiarity depended on the recollection process and remained stable over time. This study suggested that stimulus familiarity modulates the effects of category familiarity on memory performance, and clarified the boundary conditions for the effects of prior knowledge

Microstructural Abnormalities in Children with Post-traumatic Stress Disorder: A Diffusion Tensor Imaging Study at 3.0T

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder characterized by re-experiencing, avoidance and hyperarousal. Brain microstructure abnormalities in PTSD, especially in children, are not yet well characterized. The aim of this study was to use MR diffusion tensor imaging (DTI) to identify brain microstructure alterations in children with PTSD compared to non-PTSD controls who experienced the same time-limited trauma. We studied 27 children with PTSD and 24 age- and gender-matched traumatized controls without PTSD, who all experienced the 2008 Sichuan major earthquake. DTI data were acquired and analyzed in terms of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). Children with PTSD showed an abnormal pattern, not only of FA, but also of the diffusivity measures MD, AD and RD. Most of the abnormal brain regions belonged to two important networks: the default-mode network, including precuneus and angular gyrus and the salience network, including insula, putamen and thalamus. This DTI study identifies microstructural abnormalities of children with PTSD after a major earthquake, our results are consistent with the suggestion that pediatric PTSD is accompanied by a connectivity disequilibrium between the salience and default-mode networks, a finding of potential pathophysiological significance

White Matter Abnormalities in Post-traumatic Stress Disorder Following a Specific Traumatic Event

Studies of posttraumatic stress disorder (PTSD) are complicated by wide variability in the intensity and duration of prior stressors in patient participants, secondary effects of chronic psychiatric illness, and a variable history of treatment with psychiatric medications. In magnetic resonance imaging (MRI) studies, patient samples have often been small, and they were not often compared to similarly stressed patients without PTSD in order to control for general stress effects. Findings from these studies have been inconsistent. The present study investigated whole-brain microstructural alterations of white matter in a large drug-naive population who survived a specific, severe traumatic event (a major 8.0-magnitude earthquake). Using diffusion tensor imaging (DTI), we explored group differences between 88 PTSD patients and 91 matched traumatized non-PTSD controls in fractional anisotropy (FA), as well as its component elements axial diffusivity (AD) and radial diffusivity (RD), and examined these findings in relation to findings from deterministic DTI tractography. Relations between white matter alterations and psychiatric symptom severity were examined. PTSD patients, relative to similarly stressed controls, showed an FA increase as well as AD and RD changes in the white matter beneath left dorsolateral prefrontal cortex and forceps major. The observation of increased FA in the PTSD group suggests that the pathophysiology of PTSD after a specific acute traumatic event is distinct from what has been reported in patients with several years duration of illness. Alterations in dorsolateral prefrontal cortex may be an important aspect of illness pathophysiology, possibly via the region's established role in fear extinction circuitry. Use-dependent myelination or other secondary compensatory changes in response to heightened demands for threat appraisal and emotion regulation may be involved