Genetic Covariance Analysis reveals Heterogeneous Etiologic Sharing of Complex Traits: Theory, Methodology and Applications

Over the past fifteen years, genome-wide association studies (GWAS) have identified tens of thousands of single-nucleotide polymorphisms (SNPs) associated with complex human traits and diseases. Besides the success in finding risk loci, the estimation of genetic covariance based on collected GWAS data also provides insights into the genetic basis of complex traits/diseases. Genetic covariance is the covariance of genetic effects contributing to two phenotypes. Methods based on linear mixed model (LMM) in conjunction with the restricted maximum likelihood (REML) algorithm have been developed to estimate these two quantities of significant genetic interests. However, methods based on LMM have only gained middling popularity because they require individual-level genotype and phenotype data, which are usually difficult to obtain owing to policy and privacy concerns. Due to the easy access of GWAS summary statistics and computational efficiency, methods only requiring GWAS summary statistics as input have become more popular than methods utilizing individual-level genotype data. In chapter 1, we present a benchmark study for different summary-statistics-based genetic covariance estimation methods through simulation and real data applications. We focus on two major technical challenges in estimating genetic covariance: marker dependency caused by linkage disequilibrium (LD) and sample overlap between different studies. To improve the interpretability of global genetic covariance, local genetic covariance analysis could reveal heterogenous architecture of etiological sharing between complex traits and is critical for understanding the genetic basis of phenotypic correlations among traits. In chapter 2, we introduce SUPERGNOVA, a statistical framework to estimate local genetic covariance using summary statistics from genome-wide association studies. As a case study to illustrate the power of SUPERGNOVA, we performed in-depth analyses to dissect the shared genetics of ASD and cognitive abilities. Given the biological difference between two sets of genomic regions with opposite correlations between ASD and CP, we concluded that the ‘paradoxical’ genetic covariance could be explained by genetic heterogeneity. With the increasing accessibility of individual-level data from genome wide association studies, it is now common for researchers to have individual-level data of some traits in one specific population. In chapter 3, we introduce GENJI, a method that can estimate within-population or transethnic genetic covariance based on individual-level data for one trait and summary-level data for another trait. Through extensive simulations and analyses of real data on within-population and transethnic genetic correlation estimation, we show that GENJI produces more reliable and efficient estimation than summary data-based methods. This thesis first gives a review of the methods to estimate genetic covariance using summary data (chapter 1). Then, it introduces a new methodology to estimate genetic covariance in different ankles. SUPERGNOVA can estimate local genetic covariance (chapter 2) and GENJI can estimate genetic covariance jointly using individual-level data and summary data (chapter 3). We believe this thesis would be meaningful to the future research on the theory, methodology and applications of genetic covariance in human genetics

Direct Printing/Patterning of Key Components for Biosensor Devices

Recently, biosensor devices, especially wearable devices for monitoring human health, have attracted significant interests and meanwhile, they have a huge market. These wearable biosensor devices usually consist of several key components, including microfluidics, biosensing elements and power supply. Though advanced sensing platforms have been extensively explored, high manufacturing fee and lack of practical functions are the main reasons that most of devices and techniques are still out of reach for potential users. This dissertation focuses on fabricating these key components for biosensor devices via advanced printing/patterning techniques, such as inkjet-printing and nanoimprinting. These fabrication techniques can be potentially extended to roll-to-roll manufacturing system, allowing for low fabrication costs. Using UV-assisted nanoimprint lithography, flexible microfluidic devices were fabricated with thiol-ene click photopolymer on polymeric substrate. As for sensing elements, inkjet-printed electrodes were applied for electrochemical detections of multiple analytes. Here, inkjet-printed Au electrodes were applied for measuring salmonella concentration with magnetic beads. Glucose and cortisol sensing were developed with inkjet-printed graphene electrodes. These two sensors were compatible with “smart band-aid” platform for wearable monitoring. With synthetic skin, the real-time monitoring of glucose concentration was achieved, and the effect of flow rate was examined in detail. Inkjet-printed electrodes can be easily customized for various applications, though their resolutions are mostly limited to ~20 microns. It is hard to develop materials within nanoscale resolution via inkjet-printing. To develop nanostructured materials, nanoimprint lithography is introduced as a direct patterning method. Several kinds of metal oxide multilayer woodpile nanostructured electrodes were developed. The aspect ratio of the final structure can be easily customized by the number of layers. Furthermore, we examined the performance of these woodpile electrodes in electrochemical applications. For example, CeO2 woodpile electrodes were used for enzymatic glucose sensors, while TiO2 woodpile electrodes were applied as lithium-ion electrodes. The structure-processing combination can lead to efficient use of these electroactive materials. Finally, we utilized solvent-assisted nanoimprint lithography to process cellulose nanomaterials into nanostructure. Cellulose, as a major component of plant, is the most abundant biomaterial in nature. The development of patterned cellulose films can be potentially used as novel, green substrates in many applications, including wearable biosensing devices

A Class of Fractional p

We study a class of nonlinear fractional integrodifferential equations with p-Laplacian operator in Banach space. Some new existence results are obtained via fixed point theorems for nonlocal boundary value problems of fractional p-Laplacian equations. An illustrative example is also discussed

Systems and algorithms for autonomously simultaneous observation of multiple objects using robotic PTZ cameras assisted by a wide-angle camera

Abstract — We report an autonomous observation system with multiple pan-tilt-zoom (PTZ) cameras assisted by a fixed wide-angle camera. The wide-angle camera provides large but low resolution coverage and detects and tracks all moving objects in the scene. Based on the output of the wide-angle camera, the system generates spatiotemporal observation requests for each moving object, which are candidates for close-up views using PTZ cameras. Due to the fact that there are usually much more objects than the number of PTZ cameras, the system first assigns a subset of the requests/objects to each PTZ camera. The PTZ cameras then select the parameter settings that best satisfy the assigned competing requests to provide high resolution views of the moving objects. We solve the request assignment and the camera parameter selection problems in real time. The effectiveness of the proposed system is validated in comparison with an existing work using simulation. The simulation results show that in heavy traffic scenarios, our algorithm increases the number of observed objects by over 200%. I

Service requirement for terminal delivery: an empirical study from the perspective of online shoppers

To investigate customer’s service requirement for parcel delivery, combining with theoretical analysis and empirical test, a measuring model of customer service requirement was proposed for terminal delivery. Based on literature reviews, five potential dimensions with 27 items were initially discussed. Through exploratory factor analysis on samples collected from Taobao networks, four dimensions with 18 measurement items were finally confirmed including service attitude, service reliability, service standardization and service flexibility. By further confirmatory factor analysis, the fitness of this measuring model was proved to be acceptable. The research revealed that online shoppers paid attention to not only service result but also service process, so related suggestions were also proposed for express firms to promote their service management.Peer Reviewe