A Comprehensive and Universal Method for Assessing the Performance of Differential Gene Expression Analyses

The number of methods for pre-processing and analysis of gene expression data continues to increase, often making it difficult to select the most appropriate approach. We present a simple procedure for comparative estimation of a variety of methods for microarray data pre-processing and analysis. Our approach is based on the use of real microarray data in which controlled fold changes are introduced into 20% of the data to provide a metric for comparison with the unmodified data. The data modifications can be easily applied to raw data measured with any technological platform and retains all the complex structures and statistical characteristics of the real-world data. The power of the method is illustrated by its application to the quantitative comparison of different methods of normalization and analysis of microarray data. Our results demonstrate that the method of controlled modifications of real experimental data provides a simple tool for assessing the performance of data preprocessing and analysis methods

SAFety, Effectiveness of care and Resource use among Australian Hospitals (SAFER Hospitals): a protocol for a population-wide cohort study of outcomes of hospital care

First published on 20 August 2020.INTRODUCTION:Despite global concerns about the safety and quality of health care, population-wide studies of hospital outcomes are uncommon. The SAFety, Effectiveness of care and Resource use among Australian Hospitals (SAFER Hospitals) study seeks to estimate the incidence of serious adverse events, mortality, unplanned rehospitalisations and direct costs following hospital encounters using nationwide data, and to assess the variation and trends in these outcomes. METHODS AND ANALYSIS:SAFER Hospitals is a cohort study with retrospective and prospective components. The retrospective component uses data from 2012 to 2018 on all hospitalised patients age ≥18 years included in each State and Territories' Admitted Patient Collections. These routinely collected datasets record every hospital encounter from all public and most private hospitals using a standardised set of variables including patient demographics, primary and secondary diagnoses, procedures and patient status at discharge. The study outcomes are deaths, adverse events, readmissions and emergency care visits. Hospitalisation data will be linked to subsequent hospitalisations and each region's Emergency Department Data Collections and Death Registries to assess readmissions, emergency care encounters and deaths after discharge. Direct hospital costs associated with adverse outcomes will be estimated using data from the National Cost Data Collection. Variation in these outcomes among hospitals will be assessed adjusting for differences in hospitals' case-mix. The prospective component of the study will evaluate the temporal change in outcomes every 4 years from 2019 until 2030. ETHICS AND DISSEMINATION:Human Research Ethics Committees of the respective Australian states and territories provided ethical approval to conduct this study. A waiver of informed consent was granted for the use of de-identified patient data. Study findings will be disseminated via presentations at conferences and publications in peer-reviewed journals.Isuru Ranasinghe, Sadia Hossain, Anna Ali, Dennis Horton, Robert JT Adams, Bernadette Aliprandi-Costa, Christina Bertilone, Gustavo Carneiro, Martin Gallagher, Steven Guthridge, Billingsley Kaambwa, Sradha Kotwal, Gerry O'Callaghan, Ian A Scott, Renuka Visvanathan, Richard J Woodma

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.National Institutes of Health grants: (UL1RR025741, K24AR002138, P602AR30692, P01AR49084, UL1TR000165, P01AI083194, RO1AR43814, P60AR053308, UL1TR000004, AR43727, R21AI070304, RO1AR057172, UL1RR025014, R01AR051545-03, UL1RR029882, P60AR062755, P30AR53483, U19AI082714, P30GM103510, U01AI101934, AI063274, AR056360, AI083194, R37AI024717, P01083194, P01AR049084, PR094002); Northwestern University Feinberg School of Medicine; University of Alabama Birmingham; National Institute of Arthritis and Musculoskeletal and Skin Diseases; University of California Los Angeles; University of California San Francisco; Hopkins University; University of Colorado School of Medicine; University of Southern California; Seattle Children's Research Institute Arthritis Foundation; Medical University of South Carolina; Oklahoma Medical Research Foundation; Cincinnati Children's Hospital Medical Center; US Departments of Defense grant: (PR094002); Veterans Affairs; Alliance for Lupus Research; Kirkland Scholar Award; Korea Healthcare technology R & D project: (A121983); Ministry for Health and Welfare; Republic of Korea; Swedish Research Council; Instituto de Salud Carlos III grant: (PS09/00129); European Union FEDER funds; Fundação para a Ciência e Tecnologia fellowships: (SFRH/BPD/29354/2006, SFRH/BPD/34648/2007)

Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4

We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait. © 2013 Manku et al

Crop Updates 2000 - Pulses

This session covers fifty nine papers from different authors: 1.1999 PULSE INDUSTRY HIGHLIGHTS 2. CONTRIBUTORS 3. BACKGROUND 4. SUMMARY OF PREVIOUS RESULTS 5. 1999 REGIONAL ROUNDUP 6. Northern Agricultural Region, W. O’Neill, AGWEST 7. Central Agricultural Region J. Russell and R.J. French AGWEST 8. Great Southern and Lakes N. Brandon, C. Gaskin and N. Runciman, AGWEST 9. Esperance Mallee M. Seymour, AGWEST PULSE PRODUCTION AGRONOMY AND GENETIC IMPROVEMENT 10. Faba Bean 11. Desi chickpea Traits associated with drought resistance in chickpea, J. Berger, N.C. Turner, CLIMA and CSIRO Plant Industry, R.J. French, AGWEST, R. Carpenter, C. Ludwig and R. Kenney, CSIRO Plant Industry 12. Genotype x environment analysis of chickpea adaptation, J. Berger and N. Turner, CLIMA and CSIRO Plant Industry, and K.H.M. Siddique, AGWEST 13. Carbon fixation by chickpea pods under terminal drought, Q. Ma, CLIMA, M.H. Behboudian, Massey University, New Zealand, N.C. Turner and J.A. Palta, CLIMA, and CSIRO Plant Industry 14. Influence of terminal drought on growth and seed quality, M.H. Behboudian, Massey University, New Zealand, Q. Ma, CLIMA, N.C. Turner and J.A. Palta, CSIRO Plant Industry 15. Resistance to chilling at flowering and to budworm, H. Clarke, CLIMA Chickpea nodulation survey, J. Stott and J. Howieson, Centre for Rhizobium Studies, Murdoch University 16. Kabuli chickpea 17. Premium quality kabuli chickpea development in the ORIA, K.H.M. Siddique CLIMA and AGWEST, K.L. Regan, AGWEST, R. Shackles, AGWEST 18. International screening for Ascochyta blight resistance, K.H.M. Siddique CLIMA and AGWEST, C. Francis, CLIMA, K.L. Regan, AGWEST, N. Acikgoz and N. Atikyilmaz, AARI, Turkey and R.S. Malholtra, ICARDA, Syria 19. Agronomic evaluation of Ascochyta resistant kabuli germplasm in WA, K.H.M. Siddique CLIMA and AGWESTC. Francis, CLIMA, K.L. Regan and M. Baker, AGWEST 20. Field Pea 21. Lentil 22. ACIAR project J. Clements, K.H.M. Siddique CLIMA and AGWEST and C. Francis CLIMA 23. Vetch 24. Rust, M. Seymour, AGWEST 25. Narbon bean 26. Agronomy, M. Seymour, AGWEST 27. Lupinus species 28. Screening lupins for tolerance to alkaline/calcareous soils, C. Tang, CLIMA andUniversity of WAand J.D. Brand, WAITE, University of Adelaide 29. Lathyrus development, C. Hanbury and K.H.M. Siddique, CLIMA and AGWEST 30. Sheep feeding studies, C. White, CSIRO, Perth, C. Hanbury, CLIMA and K.H.M. Siddique, CLIMA and AGWEST 31. Lathyrus: a potential new ingredient in pig diets, B.P. Mullan, C.D. Hanbury and K.H.M. Siddique, AGWEST 32. Species comparison 33. Species for horticultural rotations, K.H.M. Siddique, AGWEST, R. Lancaster and I. Guthridge AGWEST 34. Marrow fat field pea shows promise in the southwest, K.H.M. Siddique, AGWEST, N. Runciman, AGWEST, and I. Pritchard, AGWEST, 35. Pulses on grey clay soils, P. Fisher, M. Braimbridge, J. Bignell, N. Brandon, R. Beermier, W. Bowden, AGWEST 36. Nutrient management of pulses 37. Summary of pulse nutrition studies in WA, M.D.A. Bolland, K.H.M. Siddique, G.P. Riethmuller, and R.F. Brennan, AGWEST 38. Pulse species response to phosphorus and zinc, S. Lawrence, Zed Rengel, University of WA, S.P. Loss, CSBP futurefarm, M.D.A. Bolland, .H.M. Siddique, W. Bowden, AGWEST 39. Gypsum 40. Antitranspirants seed priming DEMONSTRATION OF PULSES IN THE FARMING SYSTEM 41. Foliar and soil applied nutrients for field peas in the south coast mallee,M. Seymour, AGWEST, and P. Vedeniapine, Phosyn Ltd 42. Demonstration of pulse species at Kendenup, C. Kirkwood, Farmer, Katanning, R. Beermier, N. Runciman and N. Brandon, AGWEST 43. Kabuli chickpea demonstration at Gnowangerup, R. Beermier and N. Brandon, AGWEST 44. Lathyrus sativus demonstration at Mindarabin, N. Brandon and R. Beermier, AGWEST 45. New field pea varieties in the central eastern region, J. Russell, AGWEST DISEASE AND PEST MANAGEMENT 46. Ascochyta blight of chickpea 47. Botrytis grey mould (BGM) of chickpea 48. Fungal disease diagnostics, Pulse disease diagnostics, D. Wright, AGWEST Plant Laboratories 49. Viruses in pulses, Luteovirus infection in field pea and faba bean crops, and viruses in seed, L. Latham, CLIMA and AGWEST, R. Jones, AGWEST 50. Screening of pulse species for pea seed-borne mosaic virus, L. Latham, CLIMAand AGWEST, and R. Jones, AGWEST 51. CMV in chickpea: effect of seed-borne sources on virus spread and seed yield, R. Jones, AGWEST and L. Latham, CLIMA and AGWEST 52. Insect pests 53. Evaluation of transgenic field pea against the pea weevil,M.J. de Sousa Majer, School of Environmental Biology, Curtin University of Technology,, D. Hardie, and N.C. Turner, CSIRO Division of Plant Industry 54. Development of a molecular marker for pea weevil resistance in field pea, Oonagh Byrne, CLIMA, Darryl Hardie, AGWEST and Penny Smith, UWA 55. Aphid feeding damage to faba bean and lentil crops, Françoise Berlandier, AGWEST 56. Taxonomy and control of bruchids in pulses, N. Keals, CLIMA, D. Hardie and R. Emery, AGWEST, 57. ACKNOWLEDGMENTS 58. PUBLICATIONS BY PULSE PRODUCTIVITY PROJECT STAFF 59. VARIETIES PRODUCED AND COMMERCIALLY RELEASE

ABIN1 dysfunction as a genetic basis for lupus nephritis

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-?B is involved. We reported previously that aknockin mouse expressinganin active form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-?B and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases ofsystemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-?B and mitogen-activated protein kinase activity. Copyright © 2013 by the American Society of Nephrology

Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10-8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10-7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10-7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10-4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE

Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries

Objective: Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin ?M(complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. Methods: The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The singlemarker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. Results: The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88 × 10-10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32 × 10-46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91 × 10-5). Conclusion: These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE

Transancestral mapping and genetic load in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.info:eu-repo/semantics/publishedVersio

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE