High-Order SNP Combinations Associated with Complex Diseases: Efficient Discovery, Statistical Power and Functional Interactions

There has been increased interest in discovering combinations of single-nucleotide polymorphisms (SNPs) that are strongly associated with a phenotype even if each SNP has little individual effect. Efficient approaches have been proposed for searching two-locus combinations from genome-wide datasets. However, for high-order combinations, existing methods either adopt a brute-force search which only handles a small number of SNPs (up to few hundreds), or use heuristic search that may miss informative combinations. In addition, existing approaches lack statistical power because of the use of statistics with high degrees-of-freedom and the huge number of hypotheses tested during combinatorial search. Due to these challenges, functional interactions in high-order combinations have not been systematically explored. We leverage discriminative-pattern-mining algorithms from the data-mining community to search for high-order combinations in case-control datasets. The substantially improved efficiency and scalability demonstrated on synthetic and real datasets with several thousands of SNPs allows the study of several important mathematical and statistical properties of SNP combinations with order as high as eleven. We further explore functional interactions in high-order combinations and reveal a general connection between the increase in discriminative power of a combination over its subsets and the functional coherence among the genes comprising the combination, supported by multiple datasets. Finally, we study several significant high-order combinations discovered from a lung-cancer dataset and a kidney-transplant-rejection dataset in detail to provide novel insights on the complex diseases. Interestingly, many of these associations involve combinations of common variations that occur in small fractions of population. Thus, our approach is an alternative methodology for exploring the genetics of rare diseases for which the current focus is on individually rare variations

Differential Dynamics of Activity Changes in Dorsolateral and Dorsomedial Striatal Loops during Learning

The basal ganglia are implicated in a remarkable range of functions influencing emotion and cognition as well as motor behavior. Current models of basal ganglia function hypothesize that parallel limbic, associative, and motor cortico-basal ganglia loops contribute to this diverse set of functions, but little is yet known about how these loops operate and how their activities evolve during learning. To address these issues, we recorded simultaneously in sensorimotor and associative regions of the striatum as rats learned different versions of a conditional T-maze task. We found highly contrasting patterns of activity in these regions during task performance and found that these different patterns of structured activity developed concurrently, but with sharply different dynamics. Based on the region-specific dynamics of these patterns across learning, we suggest a working model whereby dorsomedial associative loops can modulate the access of dorsolateral sensorimotor loops to the control of action.National Institutes of Health (U.S.) (MH60379)United States. Office of Naval Research (N000140410208)Stanley H. and Sheila G. Sydney FundEuropean Union (Grant 201716)McGovern Institute for Brain Research at MIT (Fellowship

Learning Better Clinical Risk Models.

Risk models are used to estimate a patient’s risk of suffering particular outcomes throughout clinical practice. These models are important for matching patients to the appropriate level of treatment, for effective allocation of resources, and for fairly evaluating the performance of healthcare providers. The application and development of methods from the field of machine learning has the potential to improve patient outcomes and reduce healthcare spending with more accurate estimates of patient risk. This dissertation addresses several limitations of currently used clinical risk models, through the identification of novel risk factors and through the training of more effective models. As wearable monitors become more effective and less costly, the previously untapped predictive information in a patient’s physiology over time has the potential to greatly improve clinical practice. However translating these technological advances into real-world clinical impacts will require computational methods to identify high-risk structure in the data. This dissertation presents several approaches to learning risk factors from physiological recordings, through the discovery of latent states using topic models, and through the identification of predictive features using convolutional neural networks. We evaluate these approaches on patients from a large clinical trial and find that these methods not only outperform prior approaches to leveraging heart rate for cardiac risk stratification, but that they improve overall prediction of cardiac death when considered alongside standard clinical risk factors. We also demonstrate the utility of this work for learning a richer description of sleep recordings. Additionally, we consider the development of risk models in the presence of missing data, which is ubiquitous in real-world medical settings. We present a novel method for jointly learning risk and imputation models in the presence of missing data, and find significant improvements relative to standard approaches when evaluated on a large national registry of trauma patients.PhDComputer Science and EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113326/1/alexve_1.pd

A survey on knowledge-enhanced multimodal learning

Multimodal learning has been a field of increasing interest, aiming to combine various modalities in a single joint representation. Especially in the area of visiolinguistic (VL) learning multiple models and techniques have been developed, targeting a variety of tasks that involve images and text. VL models have reached unprecedented performances by extending the idea of Transformers, so that both modalities can learn from each other. Massive pre-training procedures enable VL models to acquire a certain level of real-world understanding, although many gaps can be identified: the limited comprehension of commonsense, factual, temporal and other everyday knowledge aspects questions the extendability of VL tasks. Knowledge graphs and other knowledge sources can fill those gaps by explicitly providing missing information, unlocking novel capabilities of VL models. In the same time, knowledge graphs enhance explainability, fairness and validity of decision making, issues of outermost importance for such complex implementations. The current survey aims to unify the fields of VL representation learning and knowledge graphs, and provides a taxonomy and analysis of knowledge-enhanced VL models