Parallel Computing with a Bayesian Item Response Model

Item response theory (IRT) is a modern test theory that has been used in various aspects of educational and psychological measurement. The fully Bayesian approach shows promise for estimating IRT models. Given that it is computationally expensive, the procedure is limited in practical applications. It is hence important to seek ways to reduce the execution time. A suitable solution is the use of high performance computing. This study focuses on the fully Bayesian algorithm for a conventional IRT model so that it can be implemented on a high performance parallel machine. Empirical results suggest that this parallel version of the algorithm achieves a considerable speedup and thus reduces the execution time considerably

A HIGH PERFORMANCE GIBBS-SAMPLING ALGORITHM FOR ITEM RESPONSE THEORY MODELS

Item response theory (IRT) is a newer and improved theory compared to the classical measurement theory. The fully Bayesian approach shows promise for IRT models. However, it is computationally expensive, and therefore is limited in various applications. It is important to seek ways to reduce the execution time and a suitable solution is the use of high performance computing (HPC). HPC offers considerably high computational power and can handle applications with high computation and memory requirements. In this work, we have modified the existing fully Bayesian algorithm for 2PNO IRT models so that it can be run on a high performance parallel machine. With this parallel version of the algorithm, the empirical results show that a speedup was achieved and the execution time was reduced considerably

Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing.

Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies

Summary of pathogenic <i>COL4A3/A4</i> mutations found in Greek-Cypriot families studied here.

<p>One additional deletion mutation was detected in a Cypriot of Romanian origin.</p><p>Summary of pathogenic <i>COL4A3/A4</i> mutations found in Greek-Cypriot families studied here.</p

Chaperone BiP protein and PERK, a transmembrane protein kinase of the PEK family resident in the endoplasmic reticulum membrane, are deregulated in AB8/13 podocytes transfected with various <i>COL4A3</i> mutant chains.

<p><b><u>a, c</u>:</b> AB8/13 cells were transiently transfected with expression vectors containing either wild-type <i>COL4A3</i> chain or one of several mutant chains. Transfection with lipofectamine only (lipo) served as a negative control. Protein expression of the UPR markers was measured 48 hours after transfection via Western blotting. β-tubulin expression in the same samples was used as equal loading control. Shown are representative blots with differential expression levels of BiP and p-PERK for the various mutant proteins. <b><u>b, d</u>:</b> Western blotting as above, was quantified via densitometric analysis. BiP and p-PERK are up-regulated in cells over-expressing the mutant <i>COL4A3</i>-p.(G1334E), <i>COL4A3</i>-p.(G871C) and <i>COL4A3</i>-p.(G484R) while there is a trend for <i>COL4A3</i>-p.(A587G), as compared to cells expressing the wild type chain. Data are means ± SEM (n = 4 for BiP; n = 7 for p-PERK) *p<0.05; **p<0.01.</p

Electropherograms showing causative mutations found in <i>COL4A3</i> (a) and in <i>COL4A4</i> (b) genes during the course of this work.

<p>In (c) is shown a 52 bp deletion in <i>COL4A4</i> which encompasses 50 bp of exon 20 plus the two conserved <b><i>gt</i></b> bp at the donor site of intron 20. In addition to the translation frameshift introduced, it is expected that aberrant splicing will occur.</p

Mutant <i>COL4A3</i> chains expressed in AB8/13 cultured podocytes demonstrate a trend for increased intracellular retention.

<p>(a) AB8/13 cells were transiently transfected with expression vectors containing wild-type <i>COL4A3</i>-WT or the mutant <i>COL4A3</i> (p.G1334E, p.G871C, p.G484R, p.A587G) cDNAs that included a HA epitope at C-terminus. Single chain expression was measured via Western blot analysis of the cell lysate, 48 h after transfection. No HA antigen was detected in AB8/13 cells transfected with a construct expressing the empty vectors. Shown is a representative Western blot of proteins in cell lysates. (b) All mutant chains show a trend towards increased intracellular retention as compared to the wild type chain, although not reaching significance at the 48 h time point. Shown is densitometry analysis data normalized to tubulin expression. Data are represented as means ± SEM of n≥3 independent experiments.</p

Mutations detected in <i>COL4A3</i> and <i>COL4A4</i> genes.

<p>*these mutations tested negative in an additional collection of 52 patients with chronic kidney disease.</p><p>**this mutation was detected only in a single patient during screening of 153 patient samples. It was subsequently detected in six of 120 Cypriot controls. It is a suspect founder mutation and is under further investigation.</p>+<p>these mutations tested negative in an additional collection of 40 patients with glomerulonephritis of unknown aetiology CY, Cypriot samples; RO, Romanian sample; ND: Not Done; NA: Not applicable.</p><p>Mutations detected in <i>COL4A3</i> and <i>COL4A4</i> genes.</p

Τable 1. Information on mutations and reagents used for their identification.

<p>If no restriction enzyme is given, detection was performed by direct Sanger DNA sequencing.</p><p>Τable 1. Information on mutations and reagents used for their identification.</p

Synonymous and non-synonymous polymorphisms detected in <i>COL4A3</i> and <i>COL4A4</i> in this work.

<p>*Polymorphisms found by NGS.</p><p>Synonymous and non-synonymous polymorphisms detected in <i>COL4A3</i> and <i>COL4A4</i> in this work.</p