Qing Lu

Yiyou Sun, Xinyang Han, Weichen Zhang et al.

Recent AI systems have achieved strong results on a wide range of benchmarks, yet these gains have not translated into economically meaningful deployment across many professional domains. We argue that this gap is largely an evaluation problem: widely used benchmarks lack sustained performance measurement on real and economically valuable workflows. This paper introduces Agents' Last Exam (ALE), a benchmark designed to evaluate AI agents on long-horizon, economically valuable, real-world tasks with verifiable outcomes. Developed in collaboration with 250+ industry experts, ALE covers non-physical industries defined with reference to O*NET / SOC 2018 (the U.S. federal occupational taxonomy). It is organized around a task taxonomy with 55 subfields grouped into 13 industry clusters covering 1K+ tasks. Current results show that the hardest tier remains far from saturated: across mainstream harness and backbone configurations, the average full pass rate is 2.6%. ALE is designed as a living benchmark: its task pool grows continuously as new workflows and industries are onboarded. More broadly, ALE is intended not merely as another leaderboard, but as an instrument for closing the gap between benchmark success and GDP-relevant impact.

Boyang Li, Qing Lu, Weiwen Jiang et al.

In most popular public accessible cryptocurrency systems, the mining pool plays a key role because mining cryptocurrency with the mining pool turns the non-profitable situation into profitable for individual miners. In many recent novel blockchain consensuses, the deep learning training procedure becomes the task for miners to prove their workload, thus the computation power of miners will not purely be spent on the hash puzzle. In this way, the hardware and energy will support the blockchain service and deep learning training simultaneously. While the incentive of miners is to earn tokens, individual miners are motivated to join mining pools to become more competitive. In this paper, we are the first to demonstrate a mining pool solution for novel consensuses based on deep learning. The mining pool manager partitions the full searching space into subspaces and all miners are scheduled to collaborate on the Neural Architecture Search (NAS) tasks in the assigned subspace. Experiments demonstrate that the performance of this type of mining pool is more competitive than an individual miner. Due to the uncertainty of miners' behaviors, the mining pool manager checks the standard deviation of the performance of high reward miners and prepares backup miners to ensure the completion of the tasks of high reward miners.

Qing Lu, Xiaowei Xu, Shunjie Dong et al.

Accurately segmenting temporal frames of cine magnetic resonance imaging (MRI) is a crucial step in various real-time MRI guided cardiac interventions. To achieve fast and accurate visual assistance, there are strict requirements on the maximum latency and minimum throughput of the segmentation framework. State-of-the-art neural networks on this task are mostly hand-crafted to satisfy these constraints while achieving high accuracy. On the other hand, while existing literature have demonstrated the power of neural architecture search (NAS) in automatically identifying the best neural architectures for various medical applications, they are mostly guided by accuracy, sometimes with computation complexity, and the importance of real-time constraints are overlooked. A major challenge is that such constraints are non-differentiable and are thus not compatible with the widely used differentiable NAS frameworks. In this paper, we present a strategy that directly handles real-time constraints in a differentiable NAS framework named RT-DNAS. Experiments on extended 2017 MICCAI ACDC dataset show that compared with state-of-the-art manually and automatically designed architectures, RT-DNAS is able to identify ones with better accuracy while satisfying the real-time constraints.

Boyang Li, Bingyu Shen, Qing Lu et al.

The continuous thriving of the Blockchain society motivates research in novel designs of schemes supporting cryptocurrencies. Previously multiple Proof-of-Deep-Learning(PoDL) consensuses have been proposed to replace hashing with useful work such as deep learning model training tasks. The energy will be more efficiently used while maintaining the ledger. However deep learning models are problem-specific and can be extremely complex. Current PoDL consensuses still require much work to realize in the real world. In this paper, we proposed a novel consensus named Proof-of-Federated-Learning-Subchain(PoFLSC) to fill the gap. We applied a subchain to record the training, challenging, and auditing activities and emphasized the importance of valuable datasets in partner selection. We simulated 20 miners in the subchain to demonstrate the effectiveness of PoFLSC. When we reduce the pool size concerning the reservation priority order, the drop rate difference in the performance in different scenarios further exhibits that the miner with a higher Shapley Value (SV) will gain a better opportunity to be selected when the size of the subchain pool is limited. In the conducted experiments, the PoFLSC consensus supported the subchain manager to be aware of reservation priority and the core partition of contributors to establish and maintain a competitive subchain.

Zi Wang, Mingkai Huang, Zhang Shi et al.

Multimodal cardiovascular magnetic resonance (CMR) imaging provides comprehensive and non-invasive insights into cardiovascular disease (CVD) diagnosis and underlying mechanisms. Despite decades of advancements, its widespread clinical adoption remains constrained by prolonged scan times and heterogeneity across medical environments. This underscores the urgent need for a generalist reconstruction foundation model for ultra-fast CMR imaging, one capable of adapting across diverse imaging scenarios and serving as the essential substrate for all downstream analyses. To enable this goal, we curate MMCMR-427K, the largest and most comprehensive multimodal CMR k-space database to date, comprising 427,465 multi-coil k-space data paired with structured metadata across 13 international centers, 12 CMR modalities, 15 scanners, and 17 CVD categories in populations across three continents. Building on this unprecedented resource, we introduce CardioMM, a generalist reconstruction foundation model capable of dynamically adapting to heterogeneous fast CMR imaging scenarios. CardioMM unifies semantic contextual understanding with physics-informed data consistency to deliver robust reconstructions across varied scanners, protocols, and patient presentations. Comprehensive evaluations demonstrate that CardioMM achieves state-of-the-art performance in the internal centers and exhibits strong zero-shot generalization to unseen external settings. Even at imaging acceleration up to 24x, CardioMM reliably preserves key cardiac phenotypes, quantitative myocardial biomarkers, and diagnostic image quality, enabling a substantial increase in CMR examination throughput without compromising clinical integrity. Together, our open-access MMCMR-427K database and CardioMM framework establish a scalable pathway toward high-throughput, high-quality, and clinically accessible cardiovascular imaging.

Jinghang Lin, Shan Zhang, Qing Lu

Transfer learning has emerged as a powerful technique in many application problems, such as computer vision and natural language processing. However, this technique is largely ignored in application to genetic data analysis. In this paper, we combine transfer learning technique with a neural network based method(expectile neural networks). With transfer learning, instead of starting the learning process from scratch, we start from one task that have been learned when solving a different task. We leverage previous learnings and avoid starting from scratch to improve the model performance by passing information gained in different but related task. To demonstrate the performance, we run two real data sets. By using transfer learning algorithm, the performance of expectile neural networks is improved compared to expectile neural network without using transfer learning technique.

Changshuai Wei, Qing Lu

Second generation sequencing technologies are being increasingly used for genetic association studies, where the main research interest is to identify sets of genetic variants that contribute to various phenotype. The phenotype can be univariate disease status, multivariate responses and even high-dimensional outcomes. Considering the genotype and phenotype as two complex objects, this also poses a general statistical problem of testing association between complex objects. We here proposed a similarity-based test, generalized similarity U (GSU), that can test the association between complex objects. We first studied the theoretical properties of the test in a general setting and then focused on the application of the test to sequencing association studies. Based on theoretical analysis, we proposed to use Laplacian kernel based similarity for GSU to boost power and enhance robustness. Through simulation, we found that GSU did have advantages over existing methods in terms of power and robustness. We further performed a whole genome sequencing (WGS) scan for Alzherimer Disease Neuroimaging Initiative (ADNI) data, identifying three genes, APOE, APOC1 and TOMM40, associated with imaging phenotype. We developed a C++ package for analysis of whole genome sequencing data using GSU. The source codes can be downloaded at https://github.com/changshuaiwei/gsu.

Olga A. Vsevolozhskaya, Dmitri V. Zaykin, Mark C. Greenwood et al.

While progress has been made in identifying common genetic variants associated with human diseases, for most of common complex diseases, the identified genetic variants only account for a small proportion of heritability. Challenges remain in finding additional unknown genetic variants predisposing to complex diseases. With the advance in next-generation sequencing technologies, sequencing studies have become commonplace in genetic research. The ongoing exome-sequencing and whole-genome-sequencing studies generate a massive amount of sequencing variants and allow researchers to comprehensively investigate their role in human diseases. The discovery of new disease-associated variants can be enhanced by utilizing powerful and computationally efficient statistical methods. In this paper, we propose a functional analysis of variance (FANOVA) method for testing an association of sequence variants in a genomic region with a qualitative trait. The FANOVA has a number of advantages: (1) it tests for a joint effect of gene variants, including both common and rare; (2) it fully utilizes linkage disequilibrium and genetic position information; and (3) allows for either protective or risk-increasing causal variants. Through simulations, we show that FANOVA outperform two popularly used methods - SKAT and a previously proposed method based on functional linear models (FLM), - especially if a sample size of a study is small and/or sequence variants have low to moderate effects. We conduct an empirical study by applying three methods (FANOVA, SKAT and FLM) to sequencing data from Dallas Heart Study. While SKAT and FLM respectively detected ANGPTL 4 and ANGPTL 3 associated with obesity, FANOVA was able to identify both genes associated with obesity.

Ming Li, Zihuai He, Min Zhang et al.

With the advance of high-throughput sequencing technologies, it has become feasible to investigate the influence of the entire spectrum of sequencing variations on complex human diseases. Although association studies utilizing the new sequencing technologies hold great promise to unravel novel genetic variants, especially rare genetic variants that contribute to human diseases, the statistical analysis of high-dimensional sequencing data remains a challenge. Advanced analytical methods are in great need to facilitate high-dimensional sequencing data analyses. In this article, we propose a generalized genetic random field (GGRF) method for association analyses of sequencing data. Like other similarity-based methods (e.g., SIMreg and SKAT), the new method has the advantages of avoiding the need to specify thresholds for rare variants and allowing for testing multiple variants acting in different directions and magnitude of effects. The method is built on the generalized estimating equation framework and thus accommodates a variety of disease phenotypes (e.g., quantitative and binary phenotypes). Moreover, it has a nice asymptotic property, and can be applied to small-scale sequencing data without need for small-sample adjustment. Through simulations, we demonstrate that the proposed GGRF attains an improved or comparable power over a commonly used method, SKAT, under various disease scenarios, especially when rare variants play a significant role in disease etiology. We further illustrate GGRF with an application to a real dataset from the Dallas Heart Study. By using GGRF, we were able to detect the association of two candidate genes, ANGPTL3 and ANGPTL4, with serum triglyceride.

Changshuai Wei, Qing Lu

Risk prediction that capitalizes on emerging genetic findings holds great promise for improving public health and clinical care. However, recent risk prediction research has shown that predictive tests formed on existing common genetic loci, including those from genome-wide association studies, have lacked sufficient accuracy for clinical use. Because most rare variants on the genome have not yet been studied for their role in risk prediction, future disease prediction discoveries should shift toward a more comprehensive risk prediction strategy that takes into account both common and rare variants. We are proposing a collapsing receiver operating characteristic CROC approach for risk prediction research on both common and rare variants. The new approach is an extension of a previously developed forward ROC FROC approach, with additional procedures for handling rare variants. The approach was evaluated through the use of 533 single-nucleotide polymorphisms SNPs in 37 candidate genes from the Genetic Analysis Workshop 17 mini-exome data set. We found that a prediction model built on all SNPs gained more accuracy AUC = 0.605 than one built on common variants alone AUC = 0.585. We further evaluated the performance of two approaches by gradually reducing the number of common variants in the analysis. We found that the CROC method attained more accuracy than the FROC method when the number of common variants in the data decreased. In an extreme scenario, when there are only rare variants in the data, the CROC reached an AUC value of 0.603, whereas the FROC had an AUC value of 0.524.

Ming Li, Ruo-Sin Peng, Changshuai Wei et al.

Variations in complex traits are influenced by multiple genetic variants, environmental risk factors, and their interactions. Though substantial progress has been made in identifying single genetic variants associated with complex traits, detecting the gene-gene and gene-environment interactions remains a great challenge. When a large number of genetic variants and environmental risk factors are involved, searching for interactions is limited to pair-wise interactions due to the exponentially increased feature space and computational intensity. Alternatively, recursive partitioning approaches, such as random forests, have gained popularity in high-dimensional genetic association studies. In this article, we propose a U-Statistic-based random forest approach, referred to as Forest U-Test, for genetic association studies with quantitative traits. Through simulation studies, we showed that the Forest U-Test outperformed existing methods. The proposed method was also applied to study Cannabis Dependence CD, using three independent datasets from the Study of Addiction: Genetics and Environment. A significant joint association was detected with an empirical p-value less than 0.001. The finding was also replicated in two independent datasets with p-values of 5.93e-19 and 4.70e-17, respectively.

Changshuai Wei, Ming Li, Yalu Wen et al.

With the advance of high-throughput genotyping and sequencing technologies, it becomes feasible to comprehensive evaluate the role of massive genetic predictors in disease prediction. There exists, therefore, a critical need for developing appropriate statistical measurements to access the combined effects of these genetic variants in disease prediction. Predictiveness curve is commonly used as a graphical tool to measure the predictive ability of a risk prediction model on a single continuous biomarker. Yet, for most complex diseases, risk prediciton models are formed on multiple genetic variants. We therefore propose a multi-marker predictiveness curve and provide a non-parametric method to construct the curve for case-control studies. We further introduce a global predictiveness U and a partial predictiveness U to summarize prediction curve across the whole population and sub-population of clinical interest, respectively. We also demonstrate the connections of predictiveness curve with ROC curve and Lorenz curve. Through simulation, we compared the performance of the predictiveness U to other three summary indices: R square, Total Gain, and Average Entropy, and showed that Predictiveness U outperformed the other three indexes in terms of unbiasedness and robustness. Moreover, we simulated a series of rare-variants disease model, found partial predictiveness U performed better than global predictiveness U. Finally, we conducted a real data analysis, using predictiveness curve and predictiveness U to evaluate a risk prediction model for Nicotine Dependence.

Tingting Hou, Chang Jiang, Qing Lu

The advent of artificial intelligence, especially the progress of deep neural networks, is expected to revolutionize genetic research and offer unprecedented potential to decode the complex relationships between genetic variants and disease phenotypes, which could mark a significant step toward improving our understanding of the disease etiology. While deep neural networks hold great promise for genetic association analysis, limited research has been focused on developing neural-network-based tests to dissect complex genotype-phenotype associations. This complexity arises from the opaque nature of neural networks and the absence of defined limiting distributions. We have previously developed a kernel-based neural network model (KNN) that synergizes the strengths of linear mixed models with conventional neural networks. KNN adopts a computationally efficient minimum norm quadratic unbiased estimator (MINQUE) algorithm and uses KNN structure to capture the complex relationship between large-scale sequencing data and a disease phenotype of interest. In the KNN framework, we introduce a MINQUE-based test to assess the joint association of genetic variants with the phenotype, which considers non-linear and non-additive effects and follows a mixture of chi-square distributions. We also construct two additional tests to evaluate and interpret linear and non-linear/non-additive genetic effects, including interaction effects. Our simulations show that our method consistently controls the type I error rate under various conditions and achieves greater power than a commonly used sequence kernel association test (SKAT), especially when involving non-linear and interaction effects. When applied to real data from the UK Biobank, our approach identified genes associated with hippocampal volume, which can be further replicated and evaluated for their role in the pathogenesis of Alzheimer's disease.

Tingting Hou, Chang Jiang, Qing Lu

The recent development of artificial intelligence (AI) technology, especially the advance of deep neural network (DNN) technology, has revolutionized many fields. While DNN plays a central role in modern AI technology, it has been rarely used in sequencing data analysis due to challenges brought by high-dimensional sequencing data (e.g., overfitting). Moreover, due to the complexity of neural networks and their unknown limiting distributions, building association tests on neural networks for genetic association analysis remains a great challenge. To address these challenges and fill the important gap of using AI in high-dimensional sequencing data analysis, we introduce a new kernel-based neural network (KNN) test for complex association analysis of sequencing data. The test is built on our previously developed KNN framework, which uses random effects to model the overall effects of high-dimensional genetic data and adopts kernel-based neural network structures to model complex genotype-phenotype relationships. Based on KNN, a Wald-type test is then introduced to evaluate the joint association of high-dimensional genetic data with a disease phenotype of interest, considering non-linear and non-additive effects (e.g., interaction effects). Through simulations, we demonstrated that our proposed method attained higher power compared to the sequence kernel association test (SKAT), especially in the presence of non-linear and interaction effects. Finally, we apply the methods to the whole genome sequencing (WGS) dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, investigating new genes associated with the hippocampal volume change over time.

Wentao Chen, Hailong Qiu, Jian Zhuang et al.

Deep neural networks (DNNs) have demonstrated their great potential in recent years, exceeding the per-formance of human experts in a wide range of applications. Due to their large sizes, however, compressiontechniques such as weight quantization and pruning are usually applied before they can be accommodated onthe edge. It is generally believed that quantization leads to performance degradation, and plenty of existingworks have explored quantization strategies aiming at minimum accuracy loss. In this paper, we argue thatquantization, which essentially imposes regularization on weight representations, can sometimes help toimprove accuracy. We conduct comprehensive experiments on three widely used applications: fully con-nected network (FCN) for biomedical image segmentation, convolutional neural network (CNN) for imageclassification on ImageNet, and recurrent neural network (RNN) for automatic speech recognition, and experi-mental results show that quantization can improve the accuracy by 1%, 1.95%, 4.23% on the three applicationsrespectively with 3.5x-6.4x memory reduction.

Muxuan Liang, Jaeyoung Park, Qing Lu et al.

Correlated outcomes are common in many practical problems. In some settings, one outcome is of particular interest, and others are auxiliary. To leverage information shared by all the outcomes, traditional multi-task learning (MTL) minimizes an averaged loss function over all the outcomes, which may lead to biased estimation for the target outcome, especially when the MTL model is mis-specified. In this work, based on a decomposition of estimation bias into two types, within-subspace and against-subspace, we develop a robust transfer learning approach to estimating a high-dimensional linear decision rule for the outcome of interest with the presence of auxiliary outcomes. The proposed method includes an MTL step using all outcomes to gain efficiency, and a subsequent calibration step using only the outcome of interest to correct both types of biases. We show that the final estimator can achieve a lower estimation error than the one using only the single outcome of interest. Simulations and real data analysis are conducted to justify the superiority of the proposed method.

Jinghang Lin, Xiaoran Tong, Chenxi Li et al.

The genetic etiologies of common diseases are highly complex and heterogeneous. Classic statistical methods, such as linear regression, have successfully identified numerous genetic variants associated with complex diseases. Nonetheless, for most complex diseases, the identified variants only account for a small proportion of heritability. Challenges remain to discover additional variants contributing to complex diseases. Expectile regression is a generalization of linear regression and provides completed information on the conditional distribution of a phenotype of interest. While expectile regression has many nice properties and holds great promise for genetic data analyses (e.g., investigating genetic variants predisposing to a high-risk population), it has been rarely used in genetic research. In this paper, we develop an expectile neural network (ENN) method for genetic data analyses of complex diseases. Similar to expectile regression, ENN provides a comprehensive view of relationships between genetic variants and disease phenotypes and can be used to discover genetic variants predisposing to sub-populations (e.g., high-risk groups). We further integrate the idea of neural networks into ENN, making it capable of capturing non-linear and non-additive genetic effects (e.g., gene-gene interactions). Through simulations, we showed that the proposed method outperformed an existing expectile regression when there exist complex relationships between genetic variants and disease phenotypes. We also applied the proposed method to the genetic data from the Study of Addiction: Genetics and Environment(SAGE), investigating the relationships of candidate genes with smoking quantity.

Song Bian, Weiwen Jiang, Qing Lu et al.

Due to increasing privacy concerns, neural network (NN) based secure inference (SI) schemes that simultaneously hide the client inputs and server models attract major research interests. While existing works focused on developing secure protocols for NN-based SI, in this work, we take a different approach. We propose NASS, an integrated framework to search for tailored NN architectures designed specifically for SI. In particular, we propose to model cryptographic protocols as design elements with associated reward functions. The characterized models are then adopted in a joint optimization with predicted hyperparameters in identifying the best NN architectures that balance prediction accuracy and execution efficiency. In the experiment, it is demonstrated that we can achieve the best of both worlds by using NASS, where the prediction accuracy can be improved from 81.6% to 84.6%, while the inference runtime is reduced by 2x and communication bandwidth by 1.9x on the CIFAR-10 dataset.

Qing Lu, Weiwen Jiang, Xiaowei Xu et al.

In the recent past, the success of Neural Architecture Search (NAS) has enabled researchers to broadly explore the design space using learning-based methods. Apart from finding better neural network architectures, the idea of automation has also inspired to improve their implementations on hardware. While some practices of hardware machine-learning automation have achieved remarkable performance, the traditional design concept is still followed: a network architecture is first structured with excellent test accuracy, and then compressed and optimized to fit into a target platform. Such a design flow will easily lead to inferior local-optimal solutions. To address this problem, we propose a new framework to jointly explore the space of neural architecture, hardware implementation, and quantization. Our objective is to find a quantized architecture with the highest accuracy that is implementable on given hardware specifications. We employ FPGAs to implement and test our designs with limited loop-up tables (LUTs) and required throughput. Compared to the separate design/searching methods, our framework has demonstrated much better performance under strict specifications and generated designs of higher accuracy by 18\% to 68\% in the task of classifying CIFAR10 images. With 30,000 LUTs, a light-weight design is found to achieve 82.98\% accuracy and 1293 images/second throughput, compared to which, under the same constraints, the traditional method even fails to find a valid solution.

Yinglu Liu, Hao Shen, Yue Si et al.

Facial landmark localization is a very crucial step in numerous face related applications, such as face recognition, facial pose estimation, face image synthesis, etc. However, previous competitions on facial landmark localization (i.e., the 300-W, 300-VW and Menpo challenges) aim to predict 68-point landmarks, which are incompetent to depict the structure of facial components. In order to overcome this problem, we construct a challenging dataset, named JD-landmark. Each image is manually annotated with 106-point landmarks. This dataset covers large variations on pose and expression, which brings a lot of difficulties to predict accurate landmarks. We hold a 106-point facial landmark localization competition1 on this dataset in conjunction with IEEE International Conference on Multimedia and Expo (ICME) 2019. The purpose of this competition is to discover effective and robust facial landmark localization approaches.

Xiaowei Xu, Qing Lu, Yu Hu et al.

With pervasive applications of medical imaging in health-care, biomedical image segmentation plays a central role in quantitative analysis, clinical diagno- sis, and medical intervention. Since manual anno- tation su ers limited reproducibility, arduous e orts, and excessive time, automatic segmentation is desired to process increasingly larger scale histopathological data. Recently, deep neural networks (DNNs), par- ticularly fully convolutional networks (FCNs), have been widely applied to biomedical image segmenta- tion, attaining much improved performance. At the same time, quantization of DNNs has become an ac- tive research topic, which aims to represent weights with less memory (precision) to considerably reduce memory and computation requirements of DNNs while maintaining acceptable accuracy. In this paper, we apply quantization techniques to FCNs for accurate biomedical image segmentation. Unlike existing litera- ture on quantization which primarily targets memory and computation complexity reduction, we apply quan- tization as a method to reduce over tting in FCNs for better accuracy. Speci cally, we focus on a state-of- the-art segmentation framework, suggestive annotation [22], which judiciously extracts representative annota- tion samples from the original training dataset, obtain- ing an e ective small-sized balanced training dataset. We develop two new quantization processes for this framework: (1) suggestive annotation with quantiza- tion for highly representative training samples, and (2) network training with quantization for high accuracy. Extensive experiments on the MICCAI Gland dataset show that both quantization processes can improve the segmentation performance, and our proposed method exceeds the current state-of-the-art performance by up to 1%. In addition, our method has a reduction of up to 6.4x on memory usage.

Changshuai Wei, Daniel J. Schaid, Qing Lu

Common complex diseases are likely influenced by the interplay of hundreds, or even thousands, of genetic variants. Converging evidence shows that genetic variants with low marginal effects (LME) play an important role in disease development. Despite their potential significance, discovering LME genetic variants and assessing their joint association on high dimensional data (e.g., genome wide association studies) remain a great challenge. To facilitate joint association analysis among a large ensemble of LME genetic variants, we proposed a computationally efficient and powerful approach, which we call Trees Assembling Mann whitney (TAMW). Through simulation studies and an empirical data application, we found that TAMW outperformed multifactor dimensionality reduction (MDR) and the likelihood ratio based Mann whitney approach (LRMW) when the underlying complex disease involves multiple LME loci and their interactions. For instance, in a simulation with 20 interacting LME loci, TAMW attained a higher power (power=0.931) than both MDR (power=0.599) and LRMW (power=0.704). In an empirical study of 29 known Crohn's disease (CD) loci, TAMW also identified a stronger joint association with CD than those detected by MDR and LRMW. Finally, we applied TAMW to Wellcome Trust CD GWAS to conduct a genome wide analysis. The analysis of 459K single nucleotide polymorphisms was completed in 40 hours using parallel computing, and revealed a joint association predisposing to CD (p-value=2.763e-19). Further analysis of the newly discovered association suggested that 13 genes, such as ATG16L1 and LACC1, may play an important role in CD pathophysiological and etiological processes.

Changshuai Wei, Ming Li, Zihuai He et al.

With advancements in next generation sequencing technology, a massive amount of sequencing data are generated, offering a great opportunity to comprehensively investigate the role of rare variants in the genetic etiology of complex diseases. Nevertheless, this poses a great challenge for the statistical analysis of high-dimensional sequencing data. The association analyses based on traditional statistical methods suffer substantial power loss because of the low frequency of genetic variants and the extremely high dimensionality of the data. We developed a weighted U statistic, referred to as WU-seq, for the high-dimensional association analysis of sequencing data. Based on a non-parametric U statistic, WU-SEQ makes no assumption of the underlying disease model and phenotype distribution, and can be applied to a variety of phenotypes. Through simulation studies and an empirical study, we showed that WU-SEQ outperformed a commonly used SKAT method when the underlying assumptions were violated (e.g., the phenotype followed a heavy-tailed distribution). Even when the assumptions were satisfied, WU-SEQ still attained comparable performance to SKAT. Finally, we applied WU-seq to sequencing data from the Dallas Heart Study (DHS), and detected an association between ANGPTL 4 and very low density lipoprotein cholesterol.

Changshuai Wei, Qing Lu

Sequencing-based studies are emerging as a major tool for genetic association studies of complex diseases. These studies pose great challenges to the traditional statistical methods (e.g., single-locus analyses based on regression methods) because of the high-dimensionality of data and the low frequency of genetic variants. In addition, there is a great interest in biology and epidemiology to identify genetic risk factors contributed to multiple disease phenotypes. The multiple phenotypes can often follow different distributions, which violates the assumptions of most current methods. In this paper, we propose a generalized similarity U test, referred to as GSU. GSU is a similarity-based test and can handle high-dimensional genotypes and phenotypes. We studied the theoretical properties of GSU, and provided the efficient p-value calculation for association test as well as the sample size and power calculation for the study design. Through simulation, we found that GSU had advantages over existing methods in terms of power and robustness to phenotype distributions. Finally, we used GSU to perform a multivariate analysis of sequencing data in the Dallas Heart Study and identified a joint association of 4 genes with 5 metabolic related phenotypes.

Changshuai Wei, Robert C. Elston, Qing Lu

Converging evidence suggests that common complex diseases with the same or similar clinical manifestations could have different underlying genetic etiologies. While current research interests have shifted toward uncovering rare variants and structural variations predisposing to human diseases, the impact of heterogeneity in genetic studies of complex diseases has been largely overlooked. Most of the existing statistical methods assume the disease under investigation has a homogeneous genetic effect and could, therefore, have low power if the disease undergoes heterogeneous pathophysiological and etiological processes. In this paper, we propose a heterogeneity weighted U (HWU) method for association analyses considering genetic heterogeneity. HWU can be applied to various types of phenotypes (e.g., binary and continuous) and is computationally effcient for high- dimensional genetic data. Through simulations, we showed the advantage of HWU when the underlying genetic etiology of a disease was heterogeneous, as well as the robustness of HWU against different model assumptions (e.g., phenotype distributions). Using HWU, we conducted a genome-wide analysis of nicotine dependence from the Study of Addiction: Genetics and Environments (SAGE) dataset. The genome-wide analysis of nearly one million genetic markers took 7 hours, identifying heterogeneous effects of two new genes (i.e., CYP3A5 and IKBKB) on nicotine dependence.