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.

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.

AI has greatly enhanced medical image analysis, yet its use in epidemiological population imaging studies remains limited due to visualization challenges in non-linear models and lack of confounder control. Addressing this, we introduce an AI method emphasizing semantic feature interpretation and resilience against multiple confounders. Our approach's merits are tested in three scenarios: extracting confounder-free features from a 2D synthetic dataset; examining the association between prenatal alcohol exposure and children's facial shapes using 3D mesh data; exploring the relationship between global cognition and brain images with a 3D MRI dataset. Results confirm our method effectively reduces confounder influences, establishing less confounded associations. Additionally, it provides a unique visual representation, highlighting specific image alterations due to identified correlations.

Although demonstrating superb performance on various NLP tasks, large language models (LLMs) still suffer from the hallucination problem, which threatens the reliability of LLMs. To measure the level of hallucination of LLMs, previous works first categorize the hallucination according to the phenomenon similarity, then quantify the proportion that model outputs contain hallucinatory contents. However, such hallucination rates could easily be distorted by confounders. Moreover, such hallucination rates could not reflect the reasons for the hallucination, as similar hallucinatory phenomena may originate from different sources. To address these issues, we propose to combine the hallucination level quantification and hallucination reason investigation through an association analysis, which builds the relationship between the hallucination rate of LLMs with a set of risk factors. In this way, we are able to observe the hallucination level under each value of each risk factor, examining the contribution and statistical significance of each risk factor, meanwhile excluding the confounding effect of other factors. Additionally, by recognizing the risk factors according to a taxonomy of model capability, we reveal a set of potential deficiencies in commonsense memorization, relational reasoning, and instruction following, which may further provide guidance for the pretraining and supervised fine-tuning process of LLMs to mitigate the hallucination.

Polygenic risk scores (PRS) estimate the genetic risk of an individual for a complex disease based on many genetic variants across the whole genome. In this study, we compared a series of computational models for estimation of breast cancer PRS. A deep neural network (DNN) was found to outperform alternative machine learning techniques and established statistical algorithms, including BLUP, BayesA and LDpred. In the test cohort with 50% prevalence, the Area Under the receiver operating characteristic Curve (AUC) were 67.4% for DNN, 64.2% for BLUP, 64.5% for BayesA, and 62.4% for LDpred. BLUP, BayesA, and LPpred all generated PRS that followed a normal distribution in the case population. However, the PRS generated by DNN in the case population followed a bi-modal distribution composed of two normal distributions with distinctly different means. This suggests that DNN was able to separate the case population into a high-genetic-risk case sub-population with an average PRS significantly higher than the control population and a normal-genetic-risk case sub-population with an average PRS similar to the control population. This allowed DNN to achieve 18.8% recall at 90% precision in the test cohort with 50% prevalence, which can be extrapolated to 65.4% recall at 20% precision in a general population with 12% prevalence. Interpretation of the DNN model identified salient variants that were assigned insignificant p-values by association studies, but were important for DNN prediction. These variants may be associated with the phenotype through non-linear relationships.

One of the most important challenges in the analysis of high-throughput genetic data is the development of efficient computational methods to identify statistically significant Single Nucleotide Polymorphisms (SNPs). Genome-wide association studies (GWAS) use single-locus analysis where each SNP is independently tested for association with phenotypes. The limitation with this approach, however, is its inability to explain genetic variation in complex diseases. Alternative approaches are required to model the intricate relationships between SNPs. Our proposed approach extends GWAS by combining deep learning stacked autoencoders (SAEs) and association rule mining (ARM) to identify epistatic interactions between SNPs. Following traditional GWAS quality control and association analysis, the most significant SNPs are selected and used in the subsequent analysis to investigate epistasis. SAERMA controls the classification results produced in the final fully connected multi-layer feedforward artificial neural network (MLP) by manipulating the interestingness measures, support and confidence, in the rule generation process. The best classification results were achieved with 204 SNPs compressed to 100 units (77% AUC, 77% SE, 68% SP, 53% Gini, logloss=0.58, and MSE=0.20), although it was possible to achieve 73% AUC (77% SE, 63% SP, 45% Gini, logloss=0.62, and MSE=0.21) with 50 hidden units - both supported by close model interpretation.

It is crucial to provide compatible treatment schemes for a disease according to various symptoms at different stages. However, most classification methods might be ineffective in accurately classifying a disease that holds the characteristics of multiple treatment stages, various symptoms, and multi-pathogenesis. Moreover, there are limited exchanges and cooperative actions in disease diagnoses and treatments between different departments and hospitals. Thus, when new diseases occur with atypical symptoms, inexperienced doctors might have difficulty in identifying them promptly and accurately. Therefore, to maximize the utilization of the advanced medical technology of developed hospitals and the rich medical knowledge of experienced doctors, a Disease Diagnosis and Treatment Recommendation System (DDTRS) is proposed in this paper. First, to effectively identify disease symptoms more accurately, a Density-Peaked Clustering Analysis (DPCA) algorithm is introduced for disease-symptom clustering. In addition, association analyses on Disease-Diagnosis (D-D) rules and Disease-Treatment (D-T) rules are conducted by the Apriori algorithm separately. The appropriate diagnosis and treatment schemes are recommended for patients and inexperienced doctors, even if they are in a limited therapeutic environment. Moreover, to reach the goals of high performance and low latency response, we implement a parallel solution for DDTRS using the Apache Spark cloud platform. Extensive experimental results demonstrate that the proposed DDTRS realizes disease-symptom clustering effectively and derives disease treatment recommendations intelligently and accurately.

Summary: Motivation: 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. Results: 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's Disease Neuroimaging Initiative (ADNI) data, identifying three genes, APOE, APOC1 and TOMM40, associated with imaging phenotype. Availability: We developed a C package for analysis of whole genome sequencing data using GSU. Contact: weichangshuai@gmail.com Key words: Weighted U Statistic; Sequencing Study; Nonparametric Statistics. 1. Introduction The ongoing sequencing studies allowed researchers to comprehensively investigate the role of a deep catalog of human genome variations in complex diseases(Cirulli and Goldstein, 2010). Although these studies hold great promise for uncovering novel disease-associated variants, the massive sequencing data bring tremendous computational and statistical challenges to data analysis. Sequencing data is characterized with high-dimensionality and sparsity, where a large portion of genetic variants are rare variants with minor allele frequency (MAF) smaller than 5%. Even with a large effect size, a rare variant is hard to detect because of its low MAF.

Summary: There are five basic styles of recommenders differentiated mostly by their core algorithms. You need to understand what's going on inside the box in order to know if you're truly optimizing this critical tool. In our first article, "Understanding and Selecting Recommenders" we talked about the broader business considerations and issues for recommenders as a group. In this article we'll cover the five basic types of recommenders and their strengths and weaknesses. Given that Recommenders add 10% to 25% of incremental income to your ecommerce business you need to know exactly how these are working. Optimization will involve fine tuning as well as potentially combining different models.

Summary: There are five basic styles of recommenders differentiated mostly by their core algorithms. You need to understand what's going on inside the box in order to know if you're truly optimizing this critical tool. In our first article, "Understanding and Selecting Recommenders" we talked about the broader business considerations and issues for recommenders as a group. In this article we'll cover the five basic types of recommenders and their strengths and weaknesses. Given that Recommenders add 10% to 25% of incremental income to your ecommerce business you need to know exactly how these are working.