bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of self-reported health & healthcare utilisation between asylum seekers and refugees: an observational study
Authors: Toar Magzoub , O'Brien Kirsty K , Fahey Tom
Published: June 2009

Background

Adult refugees and asylum seekers living in Western countries experience a high prevalence of mental health problems, especially post traumatic stress disorder (PTSD), depression and anxiety. This study compares and contrasts the prevalence of health problems, and potential risk factors as well as the utilisation of health services by asylum seekers and refugees in the Irish context.

Methods

Cross sectional study using validated self reported health status questionnaires of adult asylum seekers (n = 60) and refugees (n = 28) from 30 countries, living in Ireland. Outcome measures included: general health status (SF-36), presence of PTSD symptoms and anxiety/depression symptoms. Data on chronic conditions and pre or post migration stressors are also reported. The two groups are compared for utilisation of the health care system and the use of over the counter medications.

Results

Asylum seekers were significantly more likely than refugees to report symptoms of PTSD (OR 6.3, 95% CI: 2.2–17.9) and depression/anxiety (OR 5.8, 95% CI: 2.2–15.4), while no significant difference was found in self-reported general health. When adjusted by multivariable regression, the presence of more than one chronic disease (OR 4.0, 95%CI: 1.3–12.7; OR 3.4, 95% CI: 1.2–10.1), high levels of pre migration stressors (OR 3.6, 95% CI: 1.1–11.9; OR 3.3, 95% CI: 1.0–10.4) or post migration stressors (OR 17.3, 95% CI: 4.9–60.8; OR 3.9, 95% CI: 1.2–12.3) were independent predictors of self reported PTSD or depression/anxiety symptoms respectively, however, residence status was no longer significantly associated with PTSD or depression/anxiety. Residence status may act as a marker for other explanatory variables; our results show it has a strong relationship with post migration stressors (χ2 = 19.74, df = 1, P < 0.001).

In terms of health care utilisation, asylum seekers use GP services more often than refugees, while no significant difference was found between these groups for use of dentists, medication, hospitalisation or mental health services.

Conclusion

Asylum seekers have a higher level of self reported PTSD and depression/anxiety symptoms compared to refugees. However, residence status appears to act as a marker for post migration stressors. Compared to refugees, asylum seekers utilise GP services more often, but not mental health services.
Thoracic spine pain in the general population: Prevalence, incidence and associated factors in children, adolescents and adults. A systematic review
Authors: Briggs Andrew M , Smith Anne J , Straker Leon M , Bragge Peter
Published: June 2009

Background

Thoracic spine pain (TSP) is experienced across the lifespan by healthy individuals and is a common presentation in primary healthcare clinical practice. However, the epidemiological characteristics of TSP are not well documented compared to neck and low back pain. A rigorous evaluation of the prevalence, incidence, correlates and risk factors needs to be undertaken in order for epidemiologic data to be meaningfully used to develop evidence-based prevention and treatment recommendations for TSP.

Methods

A systematic review method was followed to report the evidence describing prevalence, incidence, associated factors and risk factors for TSP among the general population. Nine electronic databases were systematically searched to identify studies that reported either prevalence, incidence, associated factors (cross-sectional study) or risk factors (prospective study) for TSP in healthy children, adolescents or adults. Studies were evaluated for level of evidence and method quality.

Results

Of the 1389 studies identified in the literature, 33 met the inclusion criteria for this systematic review. The mean (SD) quality score (out of 15) for the included studies was 10.5 (2.0). TSP prevalence data ranged from 4.0–72.0% (point), 0.5–51.4% (7-day), 1.4–34.8% (1-month), 4.8–7.0% (3-month), 3.5–34.8% (1-year) and 15.6–19.5% (lifetime). TSP prevalence varied according to the operational definition of TSP. Prevalence for any TSP ranged from 0.5–23.0%, 15.8–34.8%, 15.0–27.5% and 12.0–31.2% for 7-day, 1-month, 1-year and lifetime periods, respectively. TSP associated with backpack use varied from 6.0–72.0% and 22.9–51.4% for point and 7-day periods, respectively. TSP interfering with school or leisure ranged from 3.5–9.7% for 1-year prevalence. Generally, studies reported a higher prevalence for TSP in child and adolescent populations, and particularly for females. The 1 month, 6 month, 1 year and 25 year incidences were 0–0.9%, 10.3%, 3.8–35.3% and 9.8% respectively. TSP was significantly associated with: concurrent musculoskeletal pain; growth and physical; lifestyle and social; backpack; postural; psychological; and environmental factors. Risk factors identified for TSP in adolescents included age (being older) and poorer mental health.

Conclusion

TSP is a common condition in the general population. While there is some evidence for biopsychosocial associations it is limited and further prospectively designed research is required to inform prevention and management strategies.
Isolation of a human-like antibody fragment (scFv) that neutralizes ricin biological activity
Authors: Pelat Thibaut , Hust Michael , Hale Martha , Lefranc Marie-Paule , Dübel Stefan , Thullier Philippe
Published: June 2009

Background

Ricin is a lethal toxin that inhibits protein synthesis. It is easily extracted from a ubiquitously grown plant, Ricinus communis, and thus readily available for use as a bioweapon (BW). Anti-ricin antibodies provide the only known therapeutic against ricin intoxication.

Results

In this study, after immunizing a non-human primate (Macaca fascicularis) with the ricin chain A (RTA), a phage-displayed immune library was built (2 × 108 clones), that included the λ light chain fragment. The library was screened against ricin, and specific binders were sequenced and further analyzed. The best clone, 43RCA, was isolated using a new, stringent neutralization test. 43RCA had a high, picomolar affinity (41 pM) and neutralized ricin efficiently (IC50 = 23 ± 3 ng/ml, corresponding to a [scFv]/[ricin] molar ratio of 4). The neutralization capacity of 43RCA compared favourably with that of polyclonal anti-deglycosylated A chain (anti-dgRCA) IgGs, obtained from hyperimmune mouse serum, which were more efficient than any monoclonal at our disposal. The 43RCA sequence is very similar to that for human IgG germline genes, with 162 of 180 identical amino acids for the VH and VL (90% sequence identity).

Conclusion

Results of the characterization studies, and the high degree of identity with human germline genes, altogether make this anti-ricin scFv, or an IgG derived from it, a likely candidate for use in humans to minimize effects caused by ricin intoxication.
The impact on neonatal mortality of shifting childbirth services among levels of hospitals: Taiwan's experience
Authors: Wang Shi-Yi , Hsu Sylvia H , Chen Li-Kuei
Published: June 2009

Background

There is considerable discussion surrounding whether advanced hospitals provide better childbirth care than local community hospitals. This study examines the effect of shifting childbirth services from advanced hospitals (i.e., medical centers and regional hospitals) to local community hospitals (i.e., clinics and district hospitals). The sample population was tracked over a seven-year period, which includes the four months of the 2003 severe acute respiratory syndrome (SARS) epidemic in Taiwan. During the SARS epidemic, pregnant women avoided using maternity services in advanced hospitals. Concerns have been raised about maintaining the quality of maternity care with increased demands on childbirth services in local community hospitals. In this study, we analyzed the impact of shifting maternity services among hospitals of different levels on neonatal mortality and maternal deaths.

Methods

A population-based study was conducted using data from Taiwan's National Health Insurance annual statistics of monthly county neonatal morality rates. Based on a pre-SARS sample from January 1998 to December 2002, we estimated a linear regression model which included "trend," a continuous variable representing the effect of yearly changes, and two binary variables, "month" and "county," controlling for seasonal and county-specific effects. With the estimated coefficients, we obtained predicted neonatal mortality rates for each county-month. We compared the differences between observed mortality rates of the SARS period and predicted rates to examine whether the shifting in maternity services during the SARS epidemic significantly affected neonatal mortality rates.

Results

With an analysis of a total of 1,848 observations between 1998 and 2004, an insignificantly negative mean of standardized predicted errors during the SARS period was found. The result of a sub-sample containing areas with advanced hospitals showed a significant negative mean of standardized predicted errors during the SARS period. These findings indicate that despite increased use of local community hospitals, neonatal mortality during the SARS epidemic did not increase, and even decreased in areas with advanced hospitals.

Conclusion

An increased use of maternity services in local community hospitals occurred during the SARS epidemic in Taiwan. However, we observed no increase in neonatal and maternity mortality associated with these increased demands on local community hospitals.
Response of tibialis anterior tendon to a chronic exposure of stretch-shortening cycles: age effects
Authors: Ensey James S , Hollander Melinda S , Wu John Z , Kashon Michael L , Baker Brent B , Cutlip Robert G
Published: June 2009

Background

The purpose of the current study was to investigate the effects of aging on tendon response to repetitive exposures of stretch-shortening cycles (SSC's).

Methods

The left hind limb from young (3 mo, N = 4) and old (30 mo, N = 9) male Fisher 344 × Brown Norway rats were exposed to 80 maximal SSCs (60 deg/s, 50 deg range of motion) 3x/week for 4.5 weeks in vivo. After the last exposure, tendons from the tibialis anterior muscle were isolated, stored at -80°C, and then tested using a micro-mechanical testing machine. Deformation of each tendon was evaluated using both relative grip-to-grip displacements and reference marks via a video system.

Results

At failure, the young control tendons had higher strain magnitude than the young exposed (p < 0.01) and the old control tendons (p < .0001). Total load at inflection was affected by age only (p < 0.01). Old exposed and control tendons exhibited significantly higher loads at the inflection point than their young counterparts (p < 0.05 for both comparisons). At failure, the old exposed tendons carried higher loads than the young exposed tendons (p < 0.05). Stiffness was affected by age only at failure where the old tendons exhibited higher stiffness in both exposed and control tendons than their young counterparts (p < 0.05 and p < 0.01, respectively).

Conclusion

The chronic protocol enhanced the elastic stiffness of young tendon and the loads in both the young and old tendons. The old exposed tendons were found to exhibit higher load capacity than their younger counterparts, which differed from our initial hypothesis.
Effects of cardiovascular lifestyle change on lipoprotein subclass profiles defined by nuclear magnetic resonance spectroscopy
Authors: Decewicz David J , Neatrour David M , Burke Amy , Haberkorn Mary Jane , Patney Heather L , Vernalis Marina N , Ellsworth Darrell L
Published: June 2009

Background

Low-density lipoprotein (LDL) cholesterol lowering is a primary goal in clinical management of patients with cardiovascular disease, but traditional cholesterol levels may not accurately reflect the true atherogenicity of plasma lipid profiles. The size and concentration of lipoprotein particles, which transport cholesterol and triglycerides, may provide additional information for accurately assessing cardiovascular risk. This study evaluated changes in plasma lipoprotein profiles determined by nuclear magnetic resonance (NMR) spectroscopy in patients participating in a prospective, nonrandomized lifestyle modification program designed to reverse or stabilize progression of coronary artery disease (CAD) to improve our understanding of lipoprotein management in cardiac patients.

Results

The lifestyle intervention was effective in producing significant changes in lipoprotein subclasses that contribute to CAD risk. There was a clear beneficial effect on the total number of LDL particles (-8.3%, p < 0.05 compared to matched controls), small dense LDL particles (-9.5%, p < 0.05), and LDL particle size (+0.8%; p < 0.05). Likewise, participants showed significant improvement in traditional CAD risk factors such as body mass index (-9.9%, p < 0.01 compared to controls), total cholesterol (-5.5%, p < 0.05), physical fitness (+37.2%, p < 0.01), and future risk for CAD (-7.9%, p < 0.01). Men and women responded differently to the program for all clinically-relevant variables, with men deriving greater benefit in terms of lipoprotein atherogenicity. Plasma lipid and lipoprotein responses to the lifestyle change program were not confounded by lipid-lowering medications.

Conclusion

In at risk patients motivated to participate, an intensive lifestyle change program can effectively alter traditional CAD risk factors and plasma lipoprotein subclasses and may reduce risk for cardiovascular events. Improvements in lipoprotein subclasses are more evident in men compared to women.
Retinal pigment epithelial cells secrete neurotrophic factors and synthesize dopamine: possible contribution to therapeutic effects of RPE cell transplantation in Parkinson's disease
Authors: Ming Ming , Li Xuping , Fan Xiaolan , Yang Dehua , Li Liang , Chen Sheng , Gu Qing , Le Weidong
Published: June 2009

Background

New strategies for the treatment of Parkinson's disease (PD) are shifted from dopamine (DA) replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE) cells as substitution for degenerated dopaminergic (DAergic) neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA.

Methods

We evaluated the protective effects of conditioned medium (CM) from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA)- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR).

Results

We report here: (1) CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2) cultured RPE cells express L-dopa decarboxylase (DDC) and synthesize DA; (3) RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4) GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues.

Conclusion

These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.
Age-related changes in arthritis susceptibility and severity in a murine model of rheumatoid arthritis
Authors: Tarjanyi Oktavia , Boldizsar Ferenc , Nemeth Peter , Mikecz Katalin , Glant Tibor T
Published: June 2009

Background

Rheumatoid arthritis (RA) most often begins in females in the fourth-fifth decade of their life, suggesting that the aging of the immune system (immunosenescence) has a major role in this disease. Therefore, in the present study, we sought to investigate the effect of age on arthritis susceptibility in BALB/c mice using the proteoglycan (PG)-induced arthritis (PGIA) model of RA.

Results

We have found that young, 1-month-old female BALB/c mice are resistant to the induction of PGIA, but with aging they become susceptible. PG-induced T cell responses decline with age, whereas there is a shift toward Th1 cytokines. An age-dependent decrease in T cell number is associated with an increased ratio of the memory phenotype, and lower CD28 expression. Antigen-presenting cells shifted from macrophages and myeloid dendritic cells in young mice toward B cells in older mice. The regulatory/activated T cell ratio decreases in older mice after PG injections indicating impaired regulation of the immune response.

Conclusion

We conclude that immunosenescence could alter arthritis susceptibility in a very complex manner including both adaptive and innate immunities, and it cannot be determined by a single trait. Cumulative alterations in immunoregulatory functions closely resemble human disease, which makes this systemic autoimmune arthritis model of RA even more valuable.
Comparison of metal-dependent catalysis by HIV-1 and ASV integrase proteins using a new and rapid, moderate throughput assay for joining activity in solution
Authors: Andrake Mark D , Ramcharan Joseph , Merkel George , Zhao Xue Zhi , Burke Terrence R , Skalka Anna Marie
Published: June 2009

Background

HIV-1 integrase (IN) is an attractive target for the development of drugs to treat AIDS, and inhibitors of this viral enzyme are already in the clinic. Nevertheless, there is a continuing need to devise new approaches to block the activity of this viral protein because of the emergence of resistant strains. To facilitate the biochemical analysis of wild-type IN and its derivatives, and to measure the potency of prospective inhibitory compounds, a rapid, moderate throughput solution assay was developed for IN-catalyzed joining of viral and target DNAs, based on the detection of a fluorescent tag.

Results

A detailed, step-by-step description of the new joining assay is provided. The reactions are run in solution, the products captured on streptavidin beads, and activity is measured by release of a fluorescent tag. The procedure can be scaled up for the analysis of numerous samples, and is substantially more rapid and sensitive than the standard radioactive gel methods. The new assay is validated and its utility demonstrated via a detailed comparison of the Mg++- and Mn++-dependent activities of the IN proteins from human immunodeficiency virus type 1 (HIV-1) and the avian sarcoma virus (ASV). The results confirm that ASV IN is considerably more active than HIV-1 IN, but with both enzymes the initial rates of joining, and the product yields, are higher in the presence of Mn++ than Mg++. Although the pH optima for these two enzymes are similar with Mn++, they differ significantly in the presence of Mg++, which is likely due to differences in the molecular environment of the binding region of this physiologically relevant divalent cation. This interpretation is strengthened by the observation that a compound that can inhibit HIV-1 IN in the presence of either metal cofactors is only effective against ASV in the presence of Mn++.

Conclusion

A simplified, assay for measuring the joining activity of retroviral IN in solution is described, which offers several advantages over previous methods and the standard radioactive gel analyses. Based on comparisons of signal to background ratios, the assay is 10–30 times more sensitive than gel analysis, allows more rapid and accurate biochemical analyses of IN catalytic activity, and moderate throughput screening of inhibitory compounds. The assay is validated, and its utility demonstrated in a comparison of the metal-dependent activities of HIV-1 and ASV IN proteins.
Habitat adaptation rather than genetic distance correlates with female preference in fire salamanders (Salamandra salamandra)
Authors: Caspers Barbara A , Junge Claudia , Weitere Markus , Steinfartz Sebastian
Published: June 2009

Background

Although some mechanisms of habitat adaptation of conspecific populations have been recently elucidated, the evolution of female preference has rarely been addressed as a force driving habitat adaptation in natural settings. Habitat adaptation of fire salamanders (Salamandra salamandra), as found in Middle Europe (Germany), can be framed in an explicit phylogeographic framework that allows for the evolution of habitat adaptation between distinct populations to be traced. Typically, females ofS. salamandraonly deposit their larvae in small permanent streams. However, some populations of the western post-glacial recolonization lineage use small temporary ponds as larval habitats. Pond larvae display several habitat-specific adaptations that are absent in stream-adapted larvae. We conducted mate preference tests with females from three distinct German populations in order to determine the influence of habitat adaptation versus neutral genetic distance on female mate choice. Two populations that we tested belong to the western post-glacial recolonization group, but are adapted to either stream or pond habitats. The third population is adapted to streams but represents the eastern recolonization lineage.

Results

Despite large genetic distances with FSTvalues around 0.5, the stream-adapted females preferred males from the same habitat type regardless of genetic distance. Conversely, pond-adapted females did not prefer males from their own population when compared to stream-adapted individuals of either lineage.

Conclusion

A comparative analysis of our data showed that habitat adaptation rather than neutral genetic distance correlates with female preference in these salamanders, and that habitat-dependent female preference of a specific pond-reproducing population may have been lost during adaptation to the novel environmental conditions of ponds.
PKC∊-Dependent Potentiation of TTX-Resistant NaV1.8 Current by Neurokinin-1 Receptor Activation in Rat Dorsal Root Ganglion Neurons
Authors: Cang Chun-Lei , Zhang Hua , Zhang Yu-Qiu , Zhao Zhi-Qi
Published: June 2009

Background

Substance P (SP), which mainly exists in a subtype of small-diameter dorsal root ganglion (DRG) neurons, is an important signal molecule in pain processing in the spinal cord. Our previous results have proved the expression of SP receptor neurokinin-1 (NK-1) on DRG neurons and its interaction with transient receptor potential vanilloid 1 (TRPV1) receptor.

Results

In this study we investigated the effect of NK-1 receptor agonist on Nav1.8, a tetrodotoxin (TTX)-resistant sodium channel, in rat small-diameter DRG neurons employing whole-cell patch clamp recordings. NK-1 agonist [Sar9, Met(O2)11]-substance P (Sar-SP) significantly enhanced the Nav1.8 currents in a subgroup of small-diameter DRG neurons under both the normal and inflammatory situation, and the enhancement was blocked by NK-1 antagonist Win51708 and protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM), but not the protein kinase A (PKA) inhibitor H89. In particular, the inhibitor of PKC∊, a PKC isoform, completely blocked this effect. Under current clamp model, Sar-SP reduced the amount of current required to evoke action potentials and increased the firing rate in a subgroup of DRG neurons.

Conclusion

These data suggest that activation of NK-1 receptor potentiates Nav1.8 sodium current via PKC∊-dependent signaling pathway, probably participating in the generation of inflammatory hyperalgesia.
N-acetylcysteine does not prevent contrast-induced nephropathy after cardiac catheterization in patients with diabetes mellitus and chronic kidney disease: a randomized clinical trial
Authors: Amini Manouchehr , Salarifar Mojtaba , Amirbaigloo Alireza , Masoudkabir Farzad , Esfahani Fatemeh
Published: June 2009

Background

Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) constitute to be a high-risk population for the development of contrast-induced nephropathy (CIN), in which the incidence of CIN is estimated to be as high as 50%. We performed this trial to assess the efficacy of N-acetylcysteine (NAC) in the prevention of this complication.

Methods

In a prospective, double-blind, placebo controlled, randomized clinical trial, we studied 90 patients undergoing elective diagnostic coronary angiography with DM and CKD (serum creatinine ≥ 1.5 mg/dL for men and ≥ 1.4 mg/dL for women). The patients were randomly assigned to receive either oral NAC (600 mg BID, starting 24 h before the procedure) or placebo, in adjunct to hydration. Serum creatinine was measured prior to and 48 h after coronary angiography. The primary end-point was the occurrence of CIN, defined as an increase in serum creatinine ≥ 0.5 mg/dL (44.2 μmol/L) or ≥ 25% above baseline at 48 h after exposure to contrast medium.

Results

Complete data on the outcomes were available on 87 patients, 45 of whom had received NAC. There were no significant differences between the NAC and placebo groups in baseline characteristics, amount of hydration, or type and volume of contrast used, except in gender (male/female, 20/25 and 34/11, respectively; P = 0.005) and the use of statins (62.2% and 37.8%, respectively; P = 0.034). CIN occurred in 5 out of 45 (11.1%) patients in the NAC group and 6 out of 42 (14.3%) patients in the placebo group (P = 0.656).

Conclusion

There was no detectable benefit for the prophylactic administration of oral NAC over an aggressive hydration protocol in patients with DM and CKD.

Trial registration

NCT00808795
Sub-typing of renal cell tumours; contribution of ancillary techniques
Authors: Pradhan Dinesh , Kakkar Nandita , Bal Amanjit , Singh Shrawan Kumar , Joshi Kusum
Published: June 2009

Background

Adult renal epithelial neoplasms are a heterogeneous group with varying prognosis and outcome requiring sub-classification.

Methods

Cases of renal cell carcinoma (RCC) in a 10 years period were analyzed with regard to the clinical features and histology. Sections were reviewed by four pathologists and the discordant cases were resolved with the help of Hale's colloidal iron stain, vimentin, CK 7, and vinculin immunostains and electron microscopy.

Results

Amongst the total of 278 cases, clear cell renal cell carcinoma was the commonest tumor with 74.8% cases, followed by papillary RCC 12.2%, chromophobe RCC 7.9%, oncocytoma 1.8%, and one case of collecting duct RCC. Eight cases were of sarcomatoid renal cell carcinoma. In 28/278 cases, diagnoses varied amongst the four pathologists and the discordance was resolved by Hale's colloidal iron stain, CK7 immunostain and electron microscopy. Vimentin and vinculin did not contribute much in differentiating subtypes of renal cell carcinomas. Relative incidence of sub-types of RCCs was compared with other series

Conclusion

To accurately subclassify renal cell carcinomas, simple ancillary techniques would possibly resolve all difficult cases. The relative incidence of sub-types of renal cell carcinoma is relatively consistent the world over. However, in India, RCCs afflict the patients two decades earlier.
Large-scale linkage analysis of 1302 affected relative pairs with rheumatoid arthritis
Authors: Hamshere Marian L , Segurado Ricardo , Moskvina Valentina , Nikolov Ivan , Glaser Beate , Holmans Peter A
Published: June 2009

Rheumatoid arthritis is the most common systematic autoimmune disease and its etiology is believed to have both strong genetic and environmental components. We demonstrate the utility of including genetic and clinical phenotypes as covariates within a linkage analysis framework to search for rheumatoid arthritis susceptibility loci. The raw genotypes of 1302 affected relative pairs were combined from four large family-based samples (North American Rheumatoid Arthritis Consortium, United Kingdom, European Consortium on Rheumatoid Arthritis Families, and Canada). The familiality of the clinical phenotypes was assessed. The affected relative pairs were subjected to autosomal multipoint affected relative-pair linkage analysis. Covariates were included in the linkage analysis to take account of heterogeneity within the sample. Evidence of familiality was observed with age at onset (p << 0.001) and rheumatoid factor (RF) IgM (p << 0.001), but not definite erosions (p = 0.21). Genome-wide significant evidence for linkage was observed on chromosome 6. Genome-wide suggestive evidence for linkage was observed on chromosomes 13 and 20 when conditioning on age at onset, chromosome 15 conditional on gender, and chromosome 19 conditional on RF IgM after allowing for multiple testing of covariates.
A genome-wide ordered-subset linkage analysis for rheumatoid arthritis
Authors: Mandhyan Desh Deep , Kim-Howard Xana , Gaines Matthew , Nath Swapan K
Published: June 2009

Rheumatoid arthritis (RA) is a chronic, complex autoimmune inflammatory disorder with poorly known etiology. Approximately 1% of the adult population is afflicted with RA. Linkage analysis of RA can be complicated by the presence of phenotypic and genetic heterogeneity. It is shown that the ordered-subset analysis (OSA) technique reduces heterogeneity, increases statistical power for detecting linkage and helps to define the most informative data set for follow-up analysis. We applied OSA to the family data from the North American Rheumatoid Arthritis Consortium study as part of the Genetic Analysis Workshop 15 (GAW15). We have incorporated two continuous covariates, 'age of onset' and 'anti-CCP level' (anti-cyclic citrinullated peptide), into our genome-wide ordered-subset linkage analysis using 809 Illumina SNP markers in 5713 individuals from 606 Caucasian RA families. A statistically significant increase in nonparametric linkage (NPL) scores was observed with covariate 'age of onset' in chromosomes 4 (p= 0.000003) and 9 (p= 0.002). With the covariate 'anti-CCP level', statistically significant increases in NPL scores were observed in chromosomes 2 (p= 0.0001), 18 (p= 0.00007), and 19 (p= 0.0003). Once we identified the linked genomic region, we then attempted to identify the best plausible parametric model at that linked locus. Our results show significant improvement in evidence for linkage and demonstrate that OSA is a useful technique to detect linkage under heterogeneity.
Bayesian hierarchical modeling of means and covariances of gene expression data within families
Authors: Pique-Regi Roger , Morrison John , Thomas Duncan C
Published: June 2009

We describe a hierarchical Bayes model for the influence of constitutional genotypes from a linkage scan on the expression of a large number of genes. The model comprises linear regression models for the means in relation to genotypes and for the covariances between pairs of related individuals in relation to their identity-by-descent estimates. The matrices of regression coefficients for all possible pairs of single-nucleotide polymorphisms (SNPs) by all possible expressed genes are in turn modeled as a mixture of null values and a normal distribution of non-null values, with probabilities and means given by a third-level model of SNP and trait random effects and a spatial regression on the distance between the SNP and the expressed gene. The latter provides a way of testing for cis and trans effects. The method was applied to data on 116 SNPs and 189 genes on chromosome 11, for which Morley et al. (Nature 2004, 430: 743–747) had previously reported linkage. We were able to confirm the association of the expression of HSD17B12 with a SNP in the same region reported by Morley et al., and also detected a SNP that appeared to affect the expression of many genes on this chromosome. The approach appears to be a promising way to address the huge multiple comparisons problem for relating genome-wide genotype × expression data.
Analysis of variation in NF-κB genes and expression levels of NF-κB-regulated molecules
Authors: Liu-Mares Wen , Sun Zhifu , Bamlet William R , Atkinson Elizabeth J , Fridley Brooke L , Slager Susan L , de Andrade Mariza , Goode Ellen L
Published: June 2009

The nuclear factor-kappaB (NF-κB) family of transcription factors regulates the expression of a variety of genes involved in apoptosis and immune response. We examined relationships between genotypes at five NF-κB subunits (NFKB1, NFKB2, REL, RELA, and RELB) and variable expression levels of 15 NF-κB regulated proteins with heritability greater than 0.40: BCL2A1, BIRC2, CD40, CD44, CD80, CFLAR, CR2, FAS, ICAM1, IL15, IRF1, JUNB, MYC, SLC2A5, and VCAM1. SNP genotypes and expression phenotypes from pedigrees of Utah residents with ancestry from northern and western Europe were provided by Genetic Analysis Workshop 15 and supplemented with additional genotype data from the International HapMap Consortium. We conducted association, linkage, and family-based association analyses between each candidate gene and the 15 heritable expression phenotypes. We observed consistent results in association and linkage analyses of the NFKB1 region (encoding p50) and levels of FAS and IRF1 expression. FAS is a cell surface protein that also belongs to the TNF-receptor family; signals through FAS are able to induce apoptosis. IRF1 is a member of the interferon regulatory transcription factor family, which has been shown to regulate apoptosis and tumor-suppression. Analyses in the REL region (encoding c-Rel) revealed linkage and association with CD40 phenotype. CD40 proteins belong to the tumor necrosis factor (TNF)-receptor family, which mediates a broad variety of immune and inflammatory responses. We conclude that variation in the genes encoding p50 and c-Rel may play a role in NF-κB-related transcription of FAS, IRF1, and CD40.
Genome-wide analysis of single-locus and epistasis single-nucleotide polymorphism effects on anti-cyclic citrullinated peptide as a measure of rheumatoid arthritis
Authors: Ma Li , Dvorkin Daniel , Garbe John R , Da Yang
Published: June 2009

The goal of this study was to identify single-locus and epistasis effects of SNP markers on anti-cyclic citrullinated peptide (anti-CCP) that is associated with rheumatoid arthritis, using the North American Rheumatoid Arthritis Consortium data. A square root transformation of the phenotypic values of anti-CCP with sex, smoking status, and a selected subset of 20 single-nucleotide polymorphism (SNP) markers in the model achieved residual normality (p> 0.05). Three single-locus effects of two SNPs were significant (p< 10-4). The epistasis analysis tested five effects of each pair of SNPs, the two-locus interaction, additive × additive, additive × dominance, dominance × additive, and dominance × dominance effects. A total of ten epistasis effects of eight pairs of SNPs on 11 autosomes and the X chromosome had significant epistasis effects (p< 10-7). Three of these epistasis effects reached significance levels ofp< 10-8,p< 10-9, andp< 10-10, respectively. Two potential SNP epistasis networks were identified. The results indicate that the genetic factors underlying anti-CCP may include single-gene action and gene interactions and that the gene-interaction mechanism underlying anti-CCP could be a complex mechanism involving pairwise epistasis effects and multiple SNPs.
Comparison of measures for haplotype similarity
Authors: Marquard Vivien , Beckmann Lars , Bermejo Justo L , Fischer Christine , Chang-Claude Jenny
Published: June 2009

Measuring the association of haplotype similarities with phenotype similarities has been used to develop statistical tests of genetic association. Previously, we applied the general approach of Mantel statistics to correlate genetic and phenotype similarity, where genetic similarity was defined by the number of intervals flanked by markers identical by state for pairs of haplotypes. Here we investigated in the case-control study design the effect on power of the Mantel statistics for five different measures of genetic similarity based on haplotypes: 1) the number of shared intervals, 2) the physical length of the shared intervals, 3) the genetic length of the shared intervals in centimorgans, 4) the genetic length of the shared intervals in linkage disequilibrium units (LDU) and 5) Yu's measure that attaches more weight to the sharing of rare than common alleles. With prior knowledge of the answers of Genetic Analysis Workshop 15 Problem 3, we analyzed the simulated data sets in two genomic regions surrounding the disease loci on chromosomes 6 and 18. For the dense map on chromosome 6, all methods showed a very high power of comparable magnitude. For chromosome 18, we observed a power between 19% and 99% at the pointwise 5% significance level using 1000 cases and 1000 controls for all methods except Yu's measure. While it yielded a much lower power, Yu's measure had 80% power around the disease locus.
Association testing by haplotype-sharing methods applicable to whole-genome analysis
Authors: Nolte Ilja M , de Vries André R , Spijker Geert T , Jansen Ritsert C , Brinza Dumitru , Zelikovsky Alexander , te Meerman Gerard J
Published: June 2009

We propose two new haplotype-sharing methods for identifying disease loci: the haplotype sharing statistic (HSS), which compares length of shared haplotypes between cases and controls, and the CROSS test, which tests whether a case and a control haplotype show less sharing than two random haplotypes. The significance of the HSS is determined using a variance estimate from the theory of U-statistics, whereas the significance of the CROSS test is estimated from a sequential randomization procedure. Both methods are fast and hence practical, even for whole-genome screens with high marker densities. We analyzed data sets of Problems 2 and 3 of Genetic Analysis Workshop 15 and compared HSS and CROSS to conventional association methods. Problem 2 provided a data set of 2300 single-nucleotide polymorphisms (SNPs) in a 10-Mb region of chromosome 18q, which had shown linkage evidence for rheumatoid arthritis. The CROSS test detected a significant association at approximately position 4407 kb. This was supported by single-marker association and HSS. The CROSS test outperformed them both with respect to significance level and signal-to-noise ratio. A 20-kb candidate region could be identified. Problem 3 provided a simulated 10 k SNP data set covering the whole genome. Three known candidate regions for rheumatoid arthritis were detected. Again, the CROSS test gave the most significant results. Furthermore, both the HSS and the CROSS showed better fine-mapping accuracy than straightforward haplotype association. In conclusion, haplotype sharing methods, particularly the CROSS test, show great promise for identifying disease gene loci.
Constructing gene association networks for rheumatoid arthritis using the backward genotype-trait association (BGTA) algorithm
Authors: Ding Yuejing , Cong Lei , Ionita-Laza Iuliana , Lo Shaw-Hwa , Zheng Tian
Published: June 2009

Background

Rheumatoid arthritis (RA, MIM 180300) is a common and complex inflammatory disorder. The North American Rheumatoid Arthritis Consortium (NARAC) data, as part of the Genetic Analysis Workshop 15 data, consists of both genome scan and candidate gene studies on RA patients.

Results

We applied the backward genotype-trait association (BGTA) algorithm to capture marginal and gene × gene interaction effects of multiple susceptibility loci on RA disease status. A two-stage screening approach was used for the genome scan, whereas a comprehensive study of all possible subsets was conducted for the candidate genes. For the genome scan, we constructed an association network among 39 genetic loci that demonstrated strong signals, 19 of which have been reported in the RA literature. For the candidate genes, we found strong signals for PTPN22 and SUMO4. Based on significant association evidence, we built an association network among the loci of PTPN22, PADI4, DLG5, SLC22A4, SUMO4, and CARD15. To control for false positives, we used permutation tests to constrain the family-wise type I error rate to 1%.

Conclusion

Using the BGTA algorithm, we identified genetic loci and candidate genes that were associated with RA susceptibility and association networks among them. For the first time, we report possible interactions between single-nucleotide polymorphisms/genes, which may be useful for biological interpretation.
Two-stage analysis strategy for identifying the IgM quantitative trait locus
Authors: Wang Tao , Lu Qing , Torres-Caban Monica , Elston Robert C
Published: June 2009

Genetic association studies offer an opportunity to find genetic variants underlying complex human diseases. Various tests have been developed to improve their power. However, none of these tests is uniformly best and it is usually unclear at the outset what test is best for a specific dataset. For example, Hotelling's T
2 test is best for normally distributed data, but it can lose considerable power when normality is not met. To achieve satisfactory power in most cases, without compromising the overall significance level, we propose to adopt a two-stage adaptive analysis strategy – several statistics are compared on a portion of the samples at the first stage and the most powerful statistic is then used for the remaining samples. We evaluated this procedure by mapping the quantitative trait locus of IgM with the simulated data in Genetic Analysis Workshop 15 Problem 3. The results show that the gain in power of the two-stage adaptive analysis procedure could be considerable when the initial choice of test statistic is wrong, whereas the loss is relatively small in the case that the optimal test chosen initially is correct.
Statistical corrections of linkage data suggest predominantly cis regulations of gene expression
Authors: Shi Jianxin , Siegmund David O , Levinson Douglas F
Published: June 2009

Morley et al. (Nature2004,430:743–747) detected significant linkages to the expression levels of 142 genes (of 3554) at a reported threshold of genome-widep= 0.001 (LOD ≈ 5.3), using 14 three-generation Centre d'Etude du Polymorphisme Humain pedigrees. Most of the linkages (77%) weretrans, i.e., more than 5 Mb from the expressed gene. However, the analysis did not account for the expected anti-conservative effect of the skewed distribution of score- or regression-based statistics in large sibships, or for the possible variance distortion due to correlations among tests. Therefore, we re-analyzed their data, using a robust score statistic for the entire pedigrees and correcting thep-values for skewness. We found that a LOD of 5.3 had a skewness-corrected genome-widep-value of 0.016 instead of 0.001 (a result that we confirmed using simulation), with around 50 expected false positives. We then further corrected for correlation among the (skew-corrected)p-values by using Efron's method for obtaining the empirical null distribution. Setting a threshold of FDR = 10% (Z= 6.4, LOD = 8.9), we detected linkage for the expression levels of 22 genes, 19 of which arecis. Limiting the analysis tocisregions, linkage was detected to the expression levels of 46 genes with 4.6 expected false positives (FDR = 10%).
Genome-wide association tests by using block information in family data
Authors: Tang Rui , Wang Fei , Sha Qiuying , Zhang Shuanglin , Chen Huann-Sheng
Published: June 2009

By applying an association test to analyze the data sets from Genetic Analysis Workshop 15 Problem 3, we compare power using different haplotype-block information. The results from using both of the two different coding schemes show that the test using tight blocks with limited haplotype diversity within each block is more powerful than that using evenly spaced blocks, and the latter is more powerful than that using single-marker blocks. By using carefully chosen haplotype blocks, the power of association tests may be enhanced.
Association mapping of susceptibility loci for rheumatoid arthritis
Authors: Kuo Tai-Yue , Lau Winston , Hu Cheng , Zhang Weihua
Published: June 2009

We analyzed a case-control data set for chromosome 18q from the Genetic Analysis Workshop 15 to detect susceptibility loci for rheumatoid arthritis (RA). A total number of 460 cases and 460 unaffected controls were genotyped on 2300 single-nucleotide polymorphisms (SNPs) by the North American Rheumatoid Arthritis Consortium. Using a multimarker approach for association mapping under the framework of the Malecot model and composite likelihood, we identified a region showing significant association with RA (p < 0.002) and the predicted disease locus was at a genomic location of 53,306 kb with a 95% confidence interval (CI) of 53,295–53,331 kb. A common haplotype in this region was protective against RA (p = 0.002). In another region showing nominal significant association (51,585 kb, 95% CI: 51,541–51,628 kb, p = 0.037), a haplotype was also protective (p = 0.002). We further demonstrated that reducing SNP density decreased power and accuracy of association mapping. SNP selection based on equal linkage disequilibrium (LD) distance generally produced higher accuracy than that based on equal kilobase distance or tagging.
Normalization of microarray expression data using within-pedigree pool and its effect on linkage analysis
Authors: Kim Yoonhee , Doan Betty Q , Duggal Priya , Bailey-Wilson Joan E
Published: June 2009

"Genetical genomics", the study of natural genetic variation combining data from genetic marker-based studies with gene expression analyses, has exploded with the recent development of advanced microarray technologies. To account for systematic variation known to exist in microarray data, it is critical to properly normalize gene expression traits before performing genetic linkage analyses. However, imposing equal means and variances across pedigrees can over-correct for the true biological variation by ignoring familial correlations in expression values. We applied the robust multiarray average (RMA) method to gene expression trait data from 14 Centre d'Etude du Polymorphisme Humain (CEPH) Utah pedigrees provided by GAW15 (Genetic Analysis Workshop 15). We compared the RMA normalization method using within-pedigree pools to RMA normalization using all individuals in a single pool, which ignores pedigree membership, and investigated the effects of these different methods on 18 gene expression traits previously found to be linked to regions containing the corresponding structural locus. Familial correlation coefficients of the expressed traits were stronger when traits were normalized within pedigrees. Surprisingly, the linkage plots for these traits were similar, suggesting that although heritability increases when traits are normalized within pedigrees, the strength of linkage evidence does not necessarily change substantially.