School of Mathematics and Statistics - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 1241
  • Item
    Thumbnail Image
    Effects of Salt Supplementation on the Albuminuric Response to Telmisartan With or Without Hydrochlorothiazide Therapy in Hypertensive Patients With Type 2 Diabetes Are Modulated by Habitual Dietary Salt Intake
    Ekinci, EI ; Thomas, G ; Thomas, D ; Johnson, C ; MacIsaac, RJ ; Houlihan, CA ; Finch, S ; Panagiotopoulos, S ; O'Callaghan, C ; Jerums, G (AMER DIABETES ASSOC, 2009-08-01)
    OBJECTIVE This prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions). RESEARCH DESIGN AND METHODS Following a washout period, subjects (n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22. RESULTS In LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% (P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure. CONCLUSIONS The AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response.
  • Item
    Thumbnail Image
    A model for analyzing clustered occurrence data
    Hwang, W-H ; Huggins, R ; Stoklosa, J (WILEY, 2021-02-15)
    Spatial or temporal clustering commonly arises in various biological and ecological applications, for example, species or communities may cluster in groups. In this paper, we develop a new clustered occurrence data model where presence-absence data are modeled under a multivariate negative binomial framework. We account for spatial or temporal clustering by introducing a community parameter in the model that controls the strength of dependence between observations thereby enhancing the estimation of the mean and dispersion parameters. We provide conditions to show the existence of maximum likelihood estimates when cluster sizes are homogeneous and equal to 2 or 3 and consider a composite likelihood approach that allows for additional robustness and flexibility in fitting for clustered occurrence data. The proposed method is evaluated in a simulation study and demonstrated using forest plot data from the Center for Tropical Forest Science. Finally, we present several examples using multiple visit occupancy data to illustrate the difference between the proposed model and those of N-mixture models.
  • Item
    Thumbnail Image
    Information content of stepped wedge designs with unequal cluster-period sizes in linear mixed models: Informing incomplete designs.
    Kasza, J ; Bowden, R ; Forbes, AB (Wiley, 2021-03-30)
    In practice, stepped wedge trials frequently include clusters of differing sizes. However, investigations into the theoretical aspects of stepped wedge designs have, until recently, typically assumed equal numbers of subjects in each cluster and in each period. The information content of the cluster-period cells, clusters, and periods of stepped wedge designs has previously been investigated assuming equal cluster-period sizes, and has shown that incomplete stepped wedge designs may be efficient alternatives to the full stepped wedge. How this changes when cluster-period sizes are not equal is unknown, and we investigate this here. Working within the linear mixed model framework, we show that the information contributed by design components (clusters, sequences, and periods) does depend on the sizes of each cluster-period. Using a particular trial that assessed the impact of an individual education intervention on log-length of stay in rehabilitation units, we demonstrate how strongly the efficiency of incomplete designs depends on which cells are excluded: smaller incomplete designs may be more powerful than alternative incomplete designs that include a greater total number of participants. This also serves to demonstrate how the pattern of information content can be used to inform a set of incomplete designs to be considered as alternatives to the complete stepped wedge design. Our theoretical results for the information content can be extended to a broad class of longitudinal (ie, multiple period) cluster randomized trial designs.
  • Item
    Thumbnail Image
    NanoSplicer: accurate identification of splice junctions using Oxford Nanopore sequencing
    You, Y ; Clark, MB ; Shim, H ; Mathelier, A (OXFORD UNIV PRESS, 2022-05-27)
    MOTIVATION: Long read sequencing methods have considerable advantages for characterising RNA isoforms. Oxford nanopore sequencing records changes in electrical current when nucleic acid traverses through a pore. However, basecalling of this raw signal (known as a squiggle) is error prone, making it challenging to accurately identify splice junctions. Existing strategies include utilising matched short-read data and/or annotated splice junctions to correct nanopore reads but add expense or limit junctions to known (incomplete) annotations. Therefore, a method that could accurately identify splice junctions solely from nanopore data would have numerous advantages. RESULTS: We developed "NanoSplicer" to identify splice junctions using raw nanopore signal (squiggles). For each splice junction the observed squiggle is compared to candidate squiggles representing potential junctions to identify the correct candidate. Measuring squiggle similarity enables us to compute the probability of each candidate junction and find the most likely one. We tested our method using 1. synthetic mRNAs with known splice junctions 2. biological mRNAs from a lung-cancer cell-line. The results from both datasets demonstrate NanoSplicer improves splice junction identification, especially when the basecalling error rate near the splice junction is elevated. AVAILABILITY AND IMPLEMENTATION: NanoSplicer is freely available at https://github.com/shimlab/NanoSplicer and has been deposited in archived format at https://doi.org/10.5281/zenodo.6403849. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
  • Item
    No Preview Available
    Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
    Blokland, GAM ; Grove, J ; Chen, C-Y ; Cotsapas, C ; Tobet, S ; Handa, R ; St Clair, D ; Lencz, T ; Mowry, BJ ; Periyasamy, S ; Cairns, MJ ; Tooney, PA ; Wu, JQ ; Kelly, B ; Kirov, G ; Sullivan, PF ; Corvin, A ; Riley, BP ; Esko, T ; Milani, L ; Jonsson, EG ; Palotie, A ; Ehrenreich, H ; Begemann, M ; Steixner-Kumar, A ; Sham, PC ; Iwata, N ; Weinberger, DR ; Gejman, P ; Sanders, AR ; Buxbaum, JD ; Rujescu, D ; Giegling, I ; Konte, B ; Hartmann, AM ; Bramon, E ; Murray, RM ; Pato, MT ; Lee, J ; Melle, I ; Molden, E ; Ophoff, RA ; McQuillin, A ; Bass, NJ ; Adolfsson, R ; Malhotra, AK ; Martin, NG ; Fullerton, JM ; Mitchell, PB ; Schofield, PR ; Forstner, AJ ; Degenhardt, F ; Schaupp, S ; Comes, AL ; Kogevinas, M ; Guzman-Parra, J ; Reif, A ; Streit, F ; Sirignano, L ; Cichon, S ; Grigoroiu-Serbanescu, M ; Hauser, J ; Lissowska, J ; Mayoral, F ; Muller-Myhsok, B ; Schulze, TG ; Nothen, MM ; Rietschel, M ; Kelsoe, J ; Leboyer, M ; Jamain, S ; Etain, B ; Bellivier, F ; Vincent, JB ; Alda, M ; O'Donovan, C ; Cervantes, P ; Biernacka, JM ; Frye, M ; McElroy, SL ; Scott, LJ ; Stahl, EA ; Landen, M ; Hamshere, ML ; Smeland, OB ; Djurovic, S ; Vaaler, AE ; Andreassen, OA ; Baune, BT ; Air, T ; Preisig, M ; Uher, R ; Levinson, DF ; Weissman, MM ; Potash, JB ; Shi, J ; Knowles, JA ; Perlis, RH ; Lucae, S ; Boomsma, D ; Penninx, BWJH ; Hottenga, J-J ; de Geus, EJC ; Willemsen, G ; Milaneschi, Y ; Tiemeier, H ; Grabe, HJ ; Teumer, A ; Van der Auwera, S ; Volker, U ; Hamilton, SP ; Magnusson, PKE ; Viktorin, A ; Mehta, D ; Mullins, N ; Adams, MJ ; Breen, G ; McIntosh, AM ; Lewis, CM ; Hougaard, DM ; Nordentoft, M ; Mors, O ; Mortensen, PB ; Werge, T ; Als, TD ; Borglum, AD ; Petryshen, TL ; Smoller, JW ; Goldstein, JM (ELSEVIER SCIENCE INC, 2021-11-29)
    BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
  • Item
    No Preview Available
    Fluctuations of the number of excursion sets of planar Gaussian fields
    Beliaev, D ; McAuley, M ; Muirhead, S (Mathematical Sciences Publishers, 2022-05-11)
  • Item
    No Preview Available
    Early life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy: a population-based cohort study.
    Mansell, T ; Saffery, R ; Burugupalli, S ; Ponsonby, A-L ; Tang, MLK ; O'Hely, M ; Bekkering, S ; Smith, AAT ; Rowland, R ; Ranganathan, S ; Sly, PD ; Vuillermin, P ; Collier, F ; Meikle, P ; Burgner, D ; Barwon Infant Study Investigator Group, (eLife Sciences Publications, Ltd, 2022-05-10)
    Background: The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation. Methods: Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used. Results: At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1. Conclusions: Infants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk. Funding: The establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women's Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).
  • Item
    No Preview Available
    Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria
    Studniberg, S ; Ioannidis, LJ ; Utami, RAS ; Trianty, L ; Liao, Y ; Abeysekera, W ; Li-Wai-Suen, CSN ; Pietrzak, HM ; Healer, J ; Puspitasari, AM ; Apriyanti, D ; Coutrier, F ; Poespoprodjo, JR ; Kenangalem, E ; Andries, B ; Prayoga, P ; Sariyanti, N ; Smyth, GK ; Cowman, AF ; Price, RN ; Noviyanti, R ; Shi, W ; Garnham, AL ; Hansen, DS (WILEY, 2022-04-01)
    Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.
  • Item
    No Preview Available
    Consecutive level spacings in the chiral Gaussian unitary ensemble: from the hard and soft edge to the bulk
    Akemann, G ; Gorski, V ; Kieburg, M (IOP Publishing Ltd, 2022-05-13)
    Abstract The local spectral statistics of random matrices forms distinct universality classes, strongly depending on the position in the spectrum. Surprisingly, the spacing between consecutive eigenvalues at the spectral edges has received little attention, where the density diverges or vanishes, respectively. This different behaviour is called hard or soft edge. We show that the spacings at the edges are almost indistinguishable from the spacing in the bulk of the spectrum. We present analytical results for consecutive spacings between the kth and (k + 1)st smallest eigenvalues in the chiral Gaussian unitary ensemble, both for finite- and large-n. The result depends on the number of the generic zero modes ν and the number of flavours N f, which are given in terms of characteristic polynomials, as motivated by quantum chromodynamics (QCD). We find that the convergence in n is very rapid. The same can be said separately about the limit k → ∞ (limit to the bulk) and ν → ∞ (limit to the soft edge). Interestingly, the Wigner surmise is a very good approximation for all these cases and, apart from k = 1, shows a deviation below one percent. These findings are corroborated with Monte-Carlo simulations. We finally compare for k = 1 with data from QCD on the lattice, being in this symmetry class.
  • Item
    No Preview Available
    Interdependence of Software and Progress of Mathematics in OR: Some Illustrative Cases and Challenges
    Kumar, S ; Munapo, E (Scientific Research Publishing, Inc., 2021)