ALGORITHMS FOR MASSIVE, EXPENSIVE, OR OTHERWISE INCONVENIENT GRAPHS

A long-standing assumption common in algorithm design is that any part of the input is accessible at any time for unit cost. However, as we work with increasingly large data sets, or as we build smaller devices, we must revisit this assumption. In this thesis, I present some of my work on graph algorithms designed for circumstances where traditional assumptions about inputs do not apply. 1. Classical graph algorithms require direct access to the input graph and this is not feasible when the graph is too large to fit in memory. For computation on massive graphs we consider the dynamic streaming graph model. Given an input graph defined by as a stream of edge insertions and deletions, our goal is to approximate properties of this graph using space that is sublinear in the size of the stream. In this thesis, I present algorithms for approximating vertex connectivity, hypergraph edge connectivity, maximum coverage, unique coverage, and temporal connectivity in graph streams. 2. In certain applications the input graph is not explicitly represented, but its edges may be discovered via queries which require costly computation or measurement. I present two open-source systems which solve real-world problems via graph algorithms which may access their inputs only through costly edge queries. M ESH is a memory manager which compacts memory efficiently by finding an approximate graph matching subject to stringent time and edge query restrictions. PathCache is an efficiently scalable network measurement platform that outperforms the current state of the art

Maximum Coverage in the Data Stream Model: Parameterized and Generalized

We present algorithms for the Max-Cover and Max-Unique-Cover problems in the data stream model. The input to both problems are $m$ subsets of a universe of size $n$ and a value $k\in [m]$. In Max-Cover, the problem is to find a collection of at most $k$ sets such that the number of elements covered by at least one set is maximized. In Max-Unique-Cover, the problem is to find a collection of at most $k$ sets such that the number of elements covered by exactly one set is maximized. Our goal is to design single-pass algorithms that use space that is sublinear in the input size. Our main algorithmic results are: If the sets have size at most $d$, there exist single-pass algorithms using $\tilde{O}(d^{d+1} k^d)$ space that solve both problems exactly. This is optimal up to polylogarithmic factors for constant $d$. If each element appears in at most $r$ sets, we present single pass algorithms using $\tilde{O}(k^2 r/\epsilon^3)$ space that return a $1+\epsilon$ approximation in the case of Max-Cover. We also present a single-pass algorithm using slightly more memory, i.e., $\tilde{O}(k^3 r/\epsilon^{4})$ space, that $1+\epsilon$ approximates Max-Unique-Cover. In contrast to the above results, when $d$ and $r$ are arbitrary, any constant pass $1+\epsilon$ approximation algorithm for either problem requires $\Omega(\epsilon^{-2}m)$ space but a single pass $O(\epsilon^{-2}mk)$ space algorithm exists. In fact any constant-pass algorithm with an approximation better than $e/(e-1)$ and $e^{1-1/k}$ for Max-Cover and Max-Unique-Cover respectively requires $\Omega(m/k^2)$ space when $d$ and $r$ are unrestricted. En route, we also obtain an algorithm for a parameterized version of the streaming Set-Cover problem.Comment: Conference version to appear at ICDT 202

Photonics

Contains reports on seven research projects.Air Force Rome Air Development Center (in collaboration with C.C. Leiby, Jr.)U.S. Air Force-Rome Air Development Center (Contract F19628-80-C-0077)National Science Foundation (Grant PHY79-09739)Joint Services Electronics Program (Contract DAAG29-80-C-0104)U.S. Air Force Geophysics Laboratory (Contract F19628-79-C-0082

Quantum Optics and Photonics

Contains reports on seven research projects.U.S. Air Force Geophysics Laboratory (Contract F19628-70-C-0082)Joint Services Electronics Program (Contract DAAG29-83-K-0003)National Science Foundation (Grant PHY82-10369)U.S. Air Force - Rome Air Development Center (in collaboration with C.C. Leiby, Jr.)U.S. Air Force - Rome Air Development Center (Contract F19628-80-C-0077)U.S. Air Force - Office of Scientific Research (Contract F49620-82-C-0091

An integrated transcriptomic and computational analysis for biomarker identification in gastric cancer

This report describes an integrated study on identification of potential markers for gastric cancer in patients’ cancer tissues and sera based on: (i) genome-scale transcriptomic analyses of 80 paired gastric cancer/reference tissues and (ii) computational prediction of blood-secretory proteins supported by experimental validation. Our findings show that: (i) 715 and 150 genes exhibit significantly differential expressions in all cancers and early-stage cancers versus reference tissues, respectively; and a substantial percentage of the alteration is found to be influenced by age and/or by gender; (ii) 21 co-expressed gene clusters have been identified, some of which are specific to certain subtypes or stages of the cancer; (iii) the top-ranked gene signatures give better than 94% classification accuracy between cancer and the reference tissues, some of which are gender-specific; and (iv) 136 of the differentially expressed genes were predicted to have their proteins secreted into blood, 81 of which were detected experimentally in the sera of 13 validation samples and 29 found to have differential abundances in the sera of cancer patients versus controls. Overall, the novel information obtained in this study has led to identification of promising diagnostic markers for gastric cancer and can benefit further analyses of the key (early) abnormalities during its development

Quantitative Magnetic Resonance Imaging in Perianal Crohn’s Disease at 1.5 and 3.0 T: A Feasibility Study

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-12, pub-electronic 2021-11-17Publication status: PublishedFunder: Medical Research Council; Grant(s): MC_PC_15033Perianal Crohn’s Disease (pCD) is a common manifestation of Crohn’s Disease. Absence of reliable disease measures makes disease monitoring unreliable. Qualitative MRI has been increasingly used for diagnosing and monitoring pCD and has shown potential for assessing response to treatment. Quantitative MRI sequences, such as diffusion-weighted imaging (DWI), dynamic contrast enhancement (DCE) and magnetisation transfer (MT), along with T2 relaxometry, offer opportunities to improve diagnostic capability. Quantitative MRI sequences (DWI, DCE, MT and T2) were used in a cohort of 25 pCD patients before and 12 weeks after biological therapy at two different field strengths (1.5 and 3 T). Disease activity was measured with the Perianal Crohn’s Disease Activity index (PDAI) and serum C-reactive protein (CRP). Diseased tissue areas on MRI were defined by a radiologist. A baseline model to predict outcome at 12 weeks was developed. No differences were seen in the quantitative MR measured in the diseased tissue regions from baseline to 12 weeks; however, PDAI and CRP decreased. Baseline PDAI, CRP, T2 relaxometry and surgical history were found to have a moderate ability to predict response after 12 weeks of biological treatment. Validation in larger cohorts with MRI and clinical measures are needed in order to further develop the model

Quantitative Magnetic Resonance Imaging in Perianal Crohn’s Disease at 1.5 and 3.0 T: A Feasibility Study

Perianal Crohn’s Disease (pCD) is a common manifestation of Crohn’s Disease. Absence of reliable disease measures makes disease monitoring unreliable. Qualitative MRI has been increasingly used for diagnosing and monitoring pCD and has shown potential for assessing response to treatment. Quantitative MRI sequences, such as diffusion-weighted imaging (DWI), dynamic contrast enhancement (DCE) and magnetisation transfer (MT), along with T2 relaxometry, offer opportunities to improve diagnostic capability. Quantitative MRI sequences (DWI, DCE, MT and T2) were used in a cohort of 25 pCD patients before and 12 weeks after biological therapy at two different field strengths (1.5 and 3 T). Disease activity was measured with the Perianal Crohn’s Disease Activity index (PDAI) and serum C-reactive protein (CRP). Diseased tissue areas on MRI were defined by a radiologist. A baseline model to predict outcome at 12 weeks was developed. No differences were seen in the quantitative MR measured in the diseased tissue regions from baseline to 12 weeks; however, PDAI and CRP decreased. Baseline PDAI, CRP, T2 relaxometry and surgical history were found to have a moderate ability to predict response after 12 weeks of biological treatment. Validation in larger cohorts with MRI and clinical measures are needed in order to further develop the model

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice