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Cover page: No semistability at infinity for Calabi-Yau metrics asymptotic to conesCreative Commons 'BY' version 4.0 license
  • Thesis
  • Peer Reviewed

Hyperkähler manifolds are one of the simplest examples of Einstein manifolds. They are Ricci-flat Riemannian manifolds with special holonomy. In dimension 4, hyperkähler 4-manifolds can be purely described by a triple of symplectic 2-forms that satisfy the pointwise orthonormal condition with respect to the wedge product.

In this dissertation, we proved the compactness of a set of hyperkähler 4-manifolds with boundary under Cheeger-Gromov topology, where we assume only geometric control on the boundary and topological conditions. We showed that our proof can be extended to Einstein 4-manifolds with boundary by assuming only additional topological conditions.

Furthermore, we discuss the period map for K3 surfaces in a differential geometric setting. We gave a simple proof for the surjectivity of the period map, without invoking Yau's theorem on the Calabi conjecture or any algebraic geometry. The key is to show that when a sequence of hyperkähler metrics has bounded period in some sense, then the sequence has a convergent subsequence under Cheeger-Gromov topology.

    Cover page: Compactness theorems on hyperkähler 4-manifolds
    • Thesis
    • Peer Reviewed

    This thesis studies a special class of Calabi-Yau metrics and singular K\"ahler-Einstein metrics that exhibit cone structures. Building on Donaldson--Sun's 2-step degeneration theory, we make progress on the precise asymptotic behavior of these metrics. The following results are proved, revealing interesting distinctions between the global and local settings.In the global setting, every complete Calabi-Yau metric with Euclidean volume growth and quadratic curvature decay, is polynomially asymptotic to its unique tangent cone at infinity. In the local setting, let $(X,p,\omega)$ be a singular K\"ahler-Einstein metric with an isolated singularity. An algebraic criterion for polynomial convergence to tangent cones is established under certain assumptions. Additionally, examples are provided where the polynomial convergence rate does not hold.

    In this thesis, we also study a special class of Hermitian-Yang-Mills connections over complete non-compact K\"ahler manifolds. We introduce the notion of stability for a pair of classes that generalizes the standard slope stability. Under the assumption that both the holomorphic vector bundle and the ambient manifold can be compactified, and the K\"ahler metric satisfies certain asymptotic behavior, we prove that this new stability condition is both sufficient and necessary for the existence of projectively Hermitian-Yang-Mills metrics.

      Cover page: On Calabi-Yau and singular K<div id=
      quot;ahler-Einstein metrics asymptotic to cones, and Hermitian-Yang-Mills connections on some complete K
      quot;ahler manifolds"/>
      • Thesis
      • Peer Reviewed

      Degenerations of Negative Kahler-Einstein Surfaces

      Aubin and Yau proved that every compact Kahler manifold with negative first Chern class admits a unique metric g such that Ric(g) =-g. Understanding how families of these metrics degenerate gives insight into their geometry and is important for understanding the compactification of the moduli space of negative Kahler-Einstein metrics. I study a special class of such families in complex dimension two. Following the work of Sun and Zhang in the Calabi-Yau case, I construct a Kahler-Einstein neck region interpolating between canonical metrics on components of the central fiber. This provides a model for the limiting geometry of metrics in the family.

        Cover page: Degenerations of Negative Kahler-Einstein Surfaces
        • Article
        • Peer Reviewed

        A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

        Background

        For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective.

        Methods

        Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function.

        Results

        Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's ϱ = 0.9) and human clinical response to vitamin B6 (ϱ = 0.93).

        Conclusions

        We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.
          Cover page: A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
          Cover page: Global Observing Needs in the Deep Ocean
          • Article
          • Peer Reviewed

          CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods

          Background

          The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors.

          Results

          Performance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic.

          Conclusions

          Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.
            Cover page: CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods