Changshuai Wei

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.

Phuc Nguyen, Benjamin Zelditch, Joyce Chen et al.

We present BanditLP, a scalable multi-stakeholder contextual bandit framework that unifies neural Thompson Sampling for learning objective-specific outcomes with a large-scale linear program for constrained action selection at serving time. The methodology is application-agnostic, compatible with arbitrary neural architectures, and deployable at web scale, with an LP solver capable of handling billions of variables. Experiments on public benchmarks and synthetic data show consistent gains over strong baselines. We apply this approach in LinkedIn's email marketing system and demonstrate business win, illustrating the value of integrated exploration and constrained optimization in production.

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.

Changshuai Wei, Benjamin Zelditch, Joyce Chen et al.

Computational marketing has become increasingly important in today's digital world, facing challenges such as massive heterogeneous data, multi-channel customer journeys, and limited marketing budgets. In this paper, we propose a general framework for marketing AI systems, the Neural Optimization with Adaptive Heuristics (NOAH) framework. NOAH is the first general framework for marketing optimization that considers both to-business (2B) and to-consumer (2C) products, as well as both owned and paid channels. We describe key modules of the NOAH framework, including prediction, optimization, and adaptive heuristics, providing examples for bidding and content optimization. We then detail the successful application of NOAH to LinkedIn's email marketing system, showcasing significant wins over the legacy ranking system. Additionally, we share details and insights that are broadly useful, particularly on: (i) addressing delayed feedback with lifetime value, (ii) performing large-scale linear programming with randomization, (iii) improving retrieval with audience expansion, (iv) reducing signal dilution in targeting tests, and (v) handling zero-inflated heavy-tail metrics in statistical testing.

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.

John Bencina, Erkut Aykutlug, Yue Chen et al.

Data Driven Attribution, which assigns conversion credits to marketing interactions based on causal patterns learned from data, is the foundation of modern marketing intelligence and vital to any marketing businesses and advertising platform. In this paper, we introduce a unified transformer-based attribution approach that can handle member-level data, aggregate-level data, and integration of external macro factors. We detail the large scale implementation of the approach at LinkedIn, showcasing significant impact. We also share learning and insights that are broadly applicable to the marketing and ad tech fields.

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.

Liyang Zhao, Olurotimi Seton, Himadeep Reddy Reddivari et al.

The sales process involves sales functions converting leads or opportunities to customers and selling more products to existing customers. The optimization of the sales process thus is key to success of any B2B business. In this work, we introduce a principled approach to sales optimization and business AI, namely the Causal Predictive Optimization and Generation, which includes three layers: 1) prediction layer with causal ML 2) optimization layer with constraint optimization and contextual bandit 3) serving layer with Generative AI and feedback-loop for system enhancement. We detail the implementation and deployment of the system in LinkedIn, showcasing significant wins over legacy systems and sharing learning and insight broadly applicable to this field.

Changshuai Wei, Phuc Nguyen, Benjamin Zelditch et al.

The standard A/B testing approaches are mostly based on t-test in large scale industry applications. These standard approaches however suffers from low statistical power in business settings, due to nature of small sample-size or non-Gaussian distribution or return-on-investment (ROI) consideration. In this paper, we propose several approaches to addresses these challenges: (i) regression adjustment, generalized estimating equation, Man-Whitney U and Zero-Trimmed U that addresses each of these issues separately, and (ii) a novel doubly robust generalized U that handles ROI consideration, distribution robustness and small samples in one framework. We provide theoretical results on asymptotic normality and efficiency bounds, together with insights on the efficiency gain from theoretical analysis. We further conduct comprehensive simulation studies and apply the methods to multiple real A/B tests.

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.