VictorJuiz/thesis huggingface dataset:
Pooled sequencing links variation in transcription factor binding and chromatin accessibility to disease risk [electronic resource]

The second chapter of this thesis focuses on identifying cis-regulatory variants that affect transcription factor (TF) binding. Broadly, we discovered thousands of cis-acting binding quantitative trait loci (bQTLs) that affect TF binding, that CTCF can recruit multiple TFs, and that bQTLs can link genetic variation to 3D-genome architecture and complex disease traits. This chapter uses a pooling-based experimental approach and a custom analysis pipeline to map QTLs that affect TF binding. Chromatin immuno-precipitation followed by high-throughput sequencing (ChIP-seq) in a population of 60-71 genotyped individuals, allows for the genetic mapping of variants affecting TF binding in a systematic way. Those variants that affect binding are likely causal for modifying the binding of the TF to the protein and are therefore, a priori more likely to affect disease phenotypes. Therefore, this framework provides a candidate molecular mechanism by which the variant is acting. The custom pipeline I developed can be used for any pooled data such as ChIP-seq, without any modifications to the pipeline. All scripts and documentation are freely available and can be found here: https://github.com/tehranchi/public . This chapter is from work published in Cell in April 2016. The third chapter uses the same pooling approach and analysis pipeline to investigate a more broad class of QTLs that affect chromatin accessibility (caQTLs). Because these caQTLs mark regions of open chromatin and subsequently actively transcribed regions, they may also contain bQTLs that modify transcription factor binding. Therefore, this approach can be used together with software that can predict TF binding in open regions to obtain a more comprehensive understanding of the binding landscape. Similar to chapter 2, this method focuses on finding cis-regulatory variants that affect chromatin accessibility. Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq) was performed in 10 global populations of genotyped individuals to allow for the mapping of variants affecting chromatin accessibility. Briefly, in this chapter we found tens of thousands of caQTLs per population, we fine-map shared caQTLs and used them to identify CTCF as the major motif relevant to open chromatin, and we find that caQTLs can link transcription factor binding to chromatin architecture and complex disease traits. This large-scale project with 1000 individuals in total, would not be tractable in the lab without pooling. Using the pooling approach drastically saves time and cost associated with sequencing and reagents. This chapter corresponds to work from a manuscript currently in prep.

Keywords: Biology.
Advisor: Fraser Hunter B. primary advisor. Thesis advisor
Petrov Dmitri Alex
Pritchard Jonathan (Jonathan K.) advisor. Thesis advisor
Snyder Michael
Poor defenses [electronic resource] : the American legal profession and the problem of the "indigent accused" in the twentieth century

This dissertation reconstructs the history of public defender offices in the United States and, more generally, the American legal profession's efforts to conceptualize and institutionalize a right to state-provided counsel in criminal cases, from the first public defender experiments beginning in the 1910s through the troubled implementation of the Supreme Court case Gideon v. Wainwright in the 1960s and 1970s. Although journalists and legal scholars have told parts of this story, this dissertation is the first historical study to piece together the story as a whole, using not just published judicial opinions and legal writings, but also a variety of archival materials, including lawyers' personal papers, correspondence, and organizational records. The dissertation argues that the problem of the "indigent accused" was both produced by and rendered ultimately insoluble by two enduring features of American law and governance, each of which has cultural, social, and political dimensions: adversarialism and federalism.

Keywords: History.
Advisor: Campbell James T. primary advisor. Thesis advisor
Gordon Robert W. (Robert Watson)
Rakove Jack N.
Post-selection inference for models characterized by quadratic constraints [electronic resource]

To address the fundamental statistical problem of conducting inference after model selection a recently developed approach conditions on the selected model and uses the corresponding truncated probability laws for inference. Though relatively simple to state, the application of this principle varies in difficulty depending on which model selection procedure is under consideration. This work identifies a general mathematical framework encompassing many model selection procedures. The simple algebra of quadratic constraints allows computation of one-dimensional truncated supports for conditional versions of standard test statistics like the chi-squared and F tests used in regression. Several important examples illustrate the utility of this framework, including forward selection with groups of variables and linear model selection with cross-validation.

Keywords: Statistics.
Advisor: Taylor Jonathan
Candès Emmanuel J. (Emmanuel Jean) advisor. Thesis advisor
Romano Joseph P.
Tibshirani Robert advisor. Thesis advisor
Power of graph-based two-sample tests [electronic resource]

Testing equality of two multivariate distributions is a classical problem for which many non-parametric tests have been proposed over the years. Most of the popular tests are based either on geometric graphs constructed using inter-point distances between the observations (multivariate generalizations of the Wald-Wolfowitz's runs test) or on multivariate data-depth (generalizations of the Mann-Whitney rank test). These tests are known to be asymptotically normal under the null and consistent against fixed alternatives. In this thesis, a general framework for graph-based tests will be introduced that includes all these tests. The asymptotic efficiency of a general graph-based test can be derived using Le Cam's theory of local asymptotic normality, which provides a theoretical basis for comparing the performances of these tests. As a consequence, it will be shown that tests based on geometric graphs such as the Friedman-Rafsky test (1979), the test based on the $K$-nearest neighbor graph (1984), the minimum matching test of Rosenbaum (2005), among others, have zero asymptotic (Pitman) efficiency against $O(N^{-\frac{1}{2}})$ alternatives. On the other hand, the tests based on multivariate depth functions (the Liu-Singh rank sum statistic (1993)), which includes the Tukey depth (1975) and the projection depth (2003), have non-zero asymptotic efficiency. Finally, the limiting normal distribution of tests based on stabilizing random geometric graphs will be derived in the Poissonized setting. This can be used to compute the power of such tests against local alternatives, which validates the various applications of these tests and provides a way to compare between tests with zero Pitman efficiency.

Keywords: Statistics.
Advisor: Diaconis Persi primary advisor. Thesis advisor
Chatterjee Sourav advisor. Thesis advisor
Friedman J. H. (Jerome H.) advisor. Thesis advisor
Holmes Susan
Precise detection of circular and linear RNA with RNA-Seq [electronic resource]

The advent of RNA-Seq initially suggested that a complete and precise reconstruction of transcriptomes, with low false positive splice site identification, would be feasible and straightforward. Although numerous RNA-Seq analysis algorithms have been developed and much progress has been made on this task, recent benchmarks by multiple groups demonstrate that significant conceptual and computational improvements are needed to improve accuracy. Highlighting the insufficiency of existing algorithms, Dr. Salzman recently discovered a new class of RNA, circular RNA, which was overlooked in spite of intensive searches for novel alternative splicing using a variety of computational approaches to analyze RNA-Seq data. Simple statistical models have improved quantification of the known transcriptome and enabled the identification of circular RNA formed from annotated exons. In this work, we developed computational and statistical algorithms for accurate detection of novel splicing events from RNA-Seq. We have developed an algorithm for the identification of annotated and novel splicing events which enabled the discovery of new features of circular RNA biology. We also developed a novel split-read approach to annotation-independent junction discovery which identifies a broad range of genomic events detectable in RNA-Seq and includes the reporting of additional features for candidate junctions that are essential for downstream statistical analysis.

Advisor: Salzman Julia
Montgomery Stephen
Plevritis Sylvia advisor. Thesis advisor
Predicting course completion in massive open online courses [electronic resource]

Between 2012 and 2016, millions of learners have enrolled in massive open online courses (MOOCs). Survey data show that most learners intended to complete their courses, but analysis of the course data shows that only a small fraction of them complete the courses. Educators are trying to support learners before they drop out, but this requires early prediction of who will complete the course and who will not. This thesis presents three techniques for predicting course completion in MOOCs based on data from three different sources: learner demographics, learner engagement with course materials, and learner interactions in course videos. The thesis shows that engagement data provide the highest prediction performance among the three data types, and that prediction performance improves the later in the course the prediction is performed. The results show that the prediction models in this thesis are a step towards in-course support of learners at risk of non-completion.

Keywords: Electrical Engineering.
Advisor: Mitchell John C. primary advisor. Thesis advisor
Girod Bernd advisor. Thesis advisor
Thille Candace advisor. Thesis advisor
Predictive ecosystem service valuation model for stakeholders in the private-sector [electronic resource]

As land development changes our built environment, natural resources are being degraded and depleted, with little knowledge of the lasting impacts. A technique to quantify the economic value of ecosystem services in a predictive method would be useful. For corporations to be more responsible, a clear business case in valuing natural systems is needed. Ecologists define the concepts of ecosystem services as the benefits that humans derive from the environment. Currently, there are no U.S. governing accounting standards for valuing ecosystem services. To determine a market price for natural capital and increasing land value of capital assets for preservation, I propose a Predictive Ecosystem Service Valuation Model. The model will integrate work from biogeochemistry with economic valuation theory. Validation of this innovative model will quantify and measure the coupling of nutrients with a valuation to assist in the operational decision-making process for corporate stakeholders.

Keywords: Civil and Environmental Engineering.
Advisor: Lepech Michael advisor. Thesis advisor
Previous selves [electronic resource] : body and narrative in Aelius Aristides' hieroi logoi and Apuleius' metamorphoses

Aelius Aristides' Hieroi Logoi and Apuleius' Metamorphoses stage prolonged encounters with the failure or refusal of one's own body to function in its capacity as a vehicle for self-presentation -- an especially important function for orators of the second century CE. Both texts explore the degree to which language can remake the narrator's fragmented world. Whereas Aristides' Hieroi Logoi contribute to the orator's healing process, Apuleius' Metamorphoses uses the imagined animal body to demonstrate the elusive nature of constituting a whole self. Throughout his Hieroi Logoi, Aristides employs metaphors to solicit his audience's participation in reconfiguring his relationship to his body and his god. Apuleius' Metamorphoses, on the other hand, dramatizes a paradox: the protagonist, Lucius, achieves his goal of literary memorialization in the form of the book we hold, and yet the self that is on display is ultimately lost to the reader.

Keywords: Classics.
Advisor: Parker Grant Richard
Stephens Susan A. primary advisor. Thesis advisor
Gleason Maud W.
Nightingale Andrea Wilson advisor. Thesis advisor
Principles of intra- and inter-species cis-regulatory variation in the primate neural crest [electronic resource]

Cis-regulatory changes play a central role in normal phenotypic variation within a species as well as in morphological divergence, yet the regulatory principles underlying emergence and modulation of human traits remain poorly understood. As part of my PhD work, I have used epigenomic profiling to annotate and explore the molecular effects of enhancer mutations using in vitro-derived neural crest cells. First, by exploiting high-frequency polymorphisms in human cell lines, we explored how mutations can cooperatively affect binding of key neural crest transcription factors at specific human enhancers. We then extended this analysis across species, using human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate divergence of craniofacial cis-regulatory landscapes genome-wide. We found that epigenomic divergence is often attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases. We further explored the properties of this cis-regulatory change, revealing the role of particular retroelements, uncovering broad clusters of species-biased enhancers near genes associated with human facial variation, and demonstrating that cis-regulatory divergence is linked to quantitative expression differences of crucial neural crest regulators. This work provides a wealth of candidates for future studies on human craniofacial development and evolution, and demonstrates the value of "cellular anthropology, " a strategy of using in-vitro-derived embryonic cell types to elucidate both fundamental and evolving mechanisms underlying morphological variation in higher primates.

Keywords: Developmental Biology.
Advisor: Wysocka Joanna
Helms Jill advisor. Thesis advisor
Kingsley David M. (David Mark) advisor. Thesis advisor
Talbot William
Priority effects in recruitment to resources between the invasive Argentine ant (Linepithema humile) and the native winter ant (Prenolepis imparis)

The Argentine ant (Linepithema humile), native to South America, has invaded areas with Mediterranean climates worldwide, displacing many native ant species. In northern California, the Argentine ant competes for the use of scale insects as a food resource with the native winter ant (Prenolepis imparis). While previous research shows that the Argentine ant recruits nestmate foragers to a food source faster than does the winter ant, the winter ant has not been completely displaced. Earlier studies show that the winter ant's chemical defenses and differences in seasonal activity may contribute to their continued coexistence. However, the behavioral mechanisms of competition for a food source have not been determined. To investigate this, we tested the effects of priority on the outcome of recruitment to a bait to determine the winner of varying trials of food source competition. In bait trials, we varied the sequence at which ants of each species arrived at the bait and the number of ants first at the bait. The results show that the effects of the order of discovery of a food source on the outcome of competition significantly determined the victor for both species. Priority by winter ants had a stronger effect on Argentine ants than the reverse. This may help to explain the continued coexistence of the two ant species, despite the recruiting success of the invasive Argentine ant. These observations, along with other studies of changing distributions of the two species in the sympatric range, suggest that the Argentine ant will not completely displace the winter ant within northern California.

Keywords:  Department of Biology
Biology
Behavioral Ecology
Invasive Species
Thesis
Advisor: Gordon Deborah
Peay Kabir
A probabilistic model of memory acceses for efficient CPU caching [electronic resource]

The memory hierarchy in a modern processor -- the main memory and different cache levels, consumes about half of the full system energy. We reduce the memory hierarchy energy by three methods: a) reducing main memory accesses by building better last level cache replacement policies, b) reducing wire energy in LLCs by doing intelligent placement and movement of data, and, c) reducing L1 access energy by performing accurate assignment of cache ways to memory access instructions. To design these policies, we propose a new model for program access patterns: the IID Sequence Model (ISM), which uses the reuse distance distributions of different cache lines. We show that a) our proposed Probabilistic Replacement Policy (PRP) reduces LLC misses by 6.6% over state-of-the-art replacement policies such as SHiP [91], b) Sub-Level Insertion Policy (SLIP), which places and moves cache lines according to their reuse distance distribution, reduces L2 energy by 35% and L3 energy by 22%, and, c) Cache Way Assignment (CWA) reduces L1D cache energy consumption by 14% by reducing way mispredictions.

Keywords: Electrical Engineering.
Advisor: Dally William J. primary advisor. Thesis advisor
Aamodt Tor M.
Rosenblum Mendel advisor. Thesis advisor
Probabilistic programming for procedural modeling and design [electronic resource]

Procedural modeling, or the use of pseudo-random programs to generate visual content, plays an important role in computer graphics and design. It facilitates content creation at massive scales, can automatically create painstakingly-detailed imagery, and can even generate pleasantly suprising results that can help people to navigate large and unintuitive design spaces. Many procedural modeling applications demand directable content---the ability to enforce aesthetic or functional constraints on model output. Bayesian inference provides a framework for such control: the procedural model specifies a generative prior, with the constraints encoded as a likelihood function. In this dissertation, we use probabilistic programming languages to express such Bayesian procedural models. A probabilistic programming language (PPL) provides random choice and Bayesian conditioning operators as primitives, and inference corresponds to searching the space of program executions for high-probability execution traces. PPLs can concisely express arbitrary probability distributions, including the complex, hierarchical, and often recursive stochastic processes required in procedural modeling. Unfortunately, PPL inference is typically inefficient, relying on expensive Monte Carlo methods. This dissertation develops a suite a of techniques for speeding up PPL inference. First, we eliminate redundant computation from Metropolis-Hastings, one of the most commonly used PPL inference algorithms. Next, we show how to efficiently explore tightly-constrained design spaces using the gradient-based, Hamiltonian Monte Carlo algorithm. Then, we address the problems posed by deep branching structures in procedural models such as recursive trees, using a new variant of Sequential Monte Carlo. Finally, we make procedural modeling programs learn from their own outputs, using neural networks that guide programs toward high-probability results with fewer samples. Together, these tools bring PPL inference closer to interactive rates, which can enable more compelling graphics and design applications.

Advisor: Goodman Noah (Noah D.) primary advisor. Thesis advisor
Hanrahan P. M. (Patrick Matthew) primary advisor. Thesis advisor
Aiken Alexander advisor. Thesis advisor
Probing the motor cortical dynamics of flexible feedback control [electronic resource]

Despite the apparent effortlessness with which we control our limbs, the physics of the skeletal muscle system that allows you to move and interact with the world are complex. Consequently, executing crisp and precise movements presents a complex control problem to the nervous system. In this thesis, we probe the neural computations in primary motor cortex (M1) and dorsal premotor cortex (PMd) that subserve reaching movements. We record neural activity using electrodes during highly controlled reaching movements performed by rhesus macaques. These neuronal population data were analyzed and modeled using techniques borrowed from the theories of dynamical systems and of dimensionality reduction. We employ both direct neuronal perturbations delivered via optogenetic activation or electrical microstimulation and mechanical perturbations of the arm facilitated by a novel, haptic reaching paradigm. We used engineered tools for observing and perturbing the neural circuits of the primate motor system, enabling dynamical models of neuronal computation to be formulated, validated, and refined. We present three major scientific results, enabled by several technical advances. First, we develop an extended array of optogenetic tools in squirrel monkeys for optical activation and inhibition of genetically and anatomically-targeted neuronal populations. Second, we utilize optogenetic activation in motor cortex of reaching macaques and analyze the robust, local neuronal dynamics which facilitate rapid recovery from this perturbation. Third, we develop an artifact rejection method which we use to directly observe the cortical response to electrical microstimulation, which we then contrast with optogenetic perturbation. Fourth, we apply ideas from optimal feedback control theory to demonstrate that the selection of task-appropriate control policies during reaching is strongly reflected in motor cortical preparatory activity. Lastly, we discuss the need for two-photon calcium imaging in awake, behaving non-human primates and report significant progress towards translating these tools from rodent models.

Keywords: Neurosciences.
Advisor: Shenoy Krishna V. (Krishna Vaughn) primary advisor. Thesis advisor
Deisseroth Karl advisor. Thesis advisor
Newsome William T. advisor. Thesis advisor
Raymond Jennifer L. advisor. Thesis advisor