Bayesian Detection of Changepoints in Finite-State Markov Chains for Multiple Sequences

We consider the analysis of sets of categorical sequences consisting of piecewise homogeneous Markov segments. The sequences are assumed to be governed by a common underlying process with segments occurring in the same order for each sequence. Segments are defined by a set of unobserved changepoints where the positions and number of changepoints can vary from sequence to sequence. We propose a Bayesian framework for analyzing such data, placing priors on the locations of the changepoints and on the transition matrices and using Markov chain Monte Carlo (MCMC) techniques to obtain posterior samples given the data. Experimental results using simulated data illustrates how the methodology can be used for inference of posterior distributions for parameters and changepoints, as well as the ability to handle considerable variability in the locations of the changepoints across different sequences. We also investigate the application of the approach to sequential data from two applications involving monsoonal rainfall patterns and branching patterns in trees

My Last Lecture

It is an honor to be selected by my peers to present the 2015 Last Lecture. Thank you Chris and Marty for you continued guidance in the tradition of the Gutenberg Conspiracy and Faculty Colloquium. Those of us who have been here for many years truly appreciate the dedication and work that goes into arranging these sessions year after year. Thank you

A Flexible Joint Longitudinal-Survival Model for Analysis of End-Stage Renal Disease Data

We propose a flexible joint longitudinal-survival framework to examine the association between longitudinally collected biomarkers and a time-to-event endpoint. More specifically, we use our method for analyzing the survival outcome of end-stage renal disease patients with time-varying serum albumin measurements. Our proposed method is robust to common parametric assumptions in that it avoids explicit distributional assumptions on longitudinal measures and allows for subject-specific baseline hazard in the survival component. Fully joint estimation is performed to account for the uncertainty in the estimated longitudinal biomarkers included in the survival model

Investigation of repeated measures linear regression methodologies

International audienc

Transcending Subjects: Hegel After Augustine, an Essay on Political Theology

From where do political reformers and radicals come who are willing and prepared to challenge the status quo? Where are people formed who are capable of initiating change within a political system? Some worry belief in transcendence closes off authentic political engagement and processes of transformation. Others think that a transcendent orientation is the only means to protect and promote a more free and just society. Some see a positive commitment to transcendence as inimical to democratic practices, while others see such a commitment as indispensible for such a project. These general issues concern transcendence, immanence, and subjectivity as they bear on the question of political transformation. Explaining the differences between these fundamental orientations prompts an investigation of the philosophical and theological systems of Hegel and Augustine. Examining Hegel and Augustine around the issues of transcendence and freedom offers a way to understand these more localized disagreements between political philosophers and theologians, and even between theologians. This dissertation examines Hegel, because after the recent demise of Kantian liberalism in the forms of Rawls and Habermas, many are returning to Hegel as the original critic of Kantian philosophy specifically, and of Enlightenment secularism generally. This return to Hegel has produced a larger amount of research that dislodges the easily caricaturized Hegel of dialectical monism and political conservativism, creating the possibility of a more positive deployment of Hegel within philosophy and politics. Concerning Augustine, in one sense his theology is perennial for theology, whether accepted or rejected. But in addition to this, just as with Hegel many are beginning to question the received Augustine, mining his texts within his own cultural and theological milieu rather than merely as the beginning of supposedly unfavorable theological developments. The time is ripe for an engagement between these two stalwarts of theology and philosophy in order to illuminate the similarities and differences and make clear their contemporary relevancy. This dissertations will argue that Hegel best represents a philosophy of ‘selftranscending immanence’ that promotes freedom by standing in opposition to transcendence, and that Augustine best respresents a theology of ‘self-immanenting transcendence’ as the only possible hope for the true freedom

Annealing of Complementary DNA Sequences During Double-Strand Break Repair in Drosophila Is Mediated by the Ortholog of SMARCAL1

DNA double-strand breaks (DSBs) pose a serious threat to genomic integrity. If unrepaired, they can lead to chromosome fragmentation and cell death. If repaired incorrectly, they can cause mutations and chromosome rearrangements. DSBs are repaired using end-joining or homology-directed repair strategies, with the predominant form of homology-directed repair being synthesis-dependent strand annealing (SDSA). SDSA is the first defense against genomic rearrangements and information loss during DSB repair, making it a vital component of cell health and an attractive target for chemotherapeutic development. SDSA has also been proposed to be the primary mechanism for integration of large insertions during genome editing with CRISPR/Cas9. Despite the central role for SDSA in genome stability, little is known about the defining step: annealing. We hypothesized that annealing during SDSA is performed by the annealing helicase SMARCAL1, which can anneal RPA-coated single DNA strands during replication-associated DNA damage repair. We used unique genetic tools in Drosophila melanogaster to test whether the fly ortholog of SMARCAL1, Marcal1, mediates annealing during SDSA. Repair that requires annealing is significantly reduced in Marcal1 null mutants in both synthesis-dependent and synthesis-independent (single-strand annealing) assays. Elimination of the ATP-binding activity of Marcal1 also reduced annealing-dependent repair, suggesting that the annealing activity requires translocation along DNA. Unlike the null mutant, however, the ATP-binding defect mutant showed reduced end joining, shedding light on the interaction between SDSA and end-joining pathways

Novel roles for the Drosophila melanogaster ortholog of SMARCAL1 in DNA damage repair

Schimke immuno-osseous dysplasia (SIOD) is a monogenic, autosomal recessive disorder with highly variable penetrance and expressivity caused by biallelic mutations in the gene SMARCAL1. SMARCAL1 and its orthologs have been implicated in multiple repair pathways including replication-associated DNA damage repair and stability, gene expression in response to environmental stress, and non-homologous end joining. Early studies of SMARCAL1 suggest a role in double strand break (DSB) repair but have not been thoroughly tested. DSBs pose a serious threat to genomic integrity. If unrepaired, they can lead to chromosome fragmentation and cell death. If repaired incorrectly, they can cause mutations and chromosome rearrangements. DSBs are repaired using end-joining or homology-directed repair strategies, with the predominant form of homology-directed repair being synthesis-dependent strand annealing (SDSA). SDSA is the first defense against genomic rearrangements and information loss during DSB repair, making it a vital component of cell health and an attractive target for chemotherapeutic development. SDSA has also been proposed to be the primary mechanism for integration of large insertions during genome editing with CRISPR/Cas9. Despite the central role for SDSA in genome stability, little is known about the defining step: annealing. I hypothesized that annealing during SDSA is performed by SMARCAL1, which can anneal RPA-coated single DNA strands during replication-associated DNA damage repair. I utilized unique genetic tools in Drosophila melanogaster to test whether the fly ortholog of SMARCAL1, Marcal1, mediates annealing during SDSA. Repair that requires annealing is significantly reduced in Marcal1 null mutants in both a synthesis-dependent and synthesis-independent (single-strand annealing) assays. Elimination of the ATP binding activity of Marcal1 also reduced annealing-dependent repair, suggesting that the annealing activity requires translocation along DNA. Unlike the null mutant, however, the ATP binding-defect mutant showed reduced end-joining, shedding light on the interaction between SDSA and end-joining pathways. Lastly, I found that Marcal1 genetically interacts with Blm in SDSA and replication-associated repair. Blm prevents replication fork damage that is often repaired via Marcal1-mediated pathways. These data contribute to our understanding of DNA damage repair mechanisms and regulation.Doctor of Philosoph