The transplant iron score as a predictor of stem cell transplant survival

Recent studies have suggested that the presence of iron overload prior to stem cell transplantation is associated with decreased survival. Within these studies, the criteria used to define iron overload have varied considerably. Given the lack of consensus regarding the definition of iron overload in the transplant setting, we sought to methodically examine iron status among transplant patients. We studied 78 consecutive patients at risk for transfusion-related iron overload (diagnoses included AML, ALL, MDS, and aplastic anemia) who received either autologous or allogeneic stem cell transplant. Multiple measures of iron status were collected prior to transplantation and examined for their association with survival. Using this data, three potentially prognostic iron measures were identified and incorporated into a rational and unified scoring system. The resulting Transplant Iron Score assigns a point for each of the following variables: (1) greater than 25 red cell units transfused prior to transplantation; (2) serum ferritin > 1000 ng/ml; and (3) a semi-quantitative bone marrow iron stain of 6+. In our cohort, the score (range 0 to 3) was more closely associated with survival than any available single iron parameter. In multivariate analysis, we observed an independent effect of iron overload on transplant survival (p = 0.01) primarily attributable to an increase in early treatment-related deaths (p = 0.02) and lethal infections. In subgroup analysis, the predictive power of the iron score was most pronounced among allogeneic transplant patients, where a high score (≥ 2) was associated with a 50% absolute decrease in survival at one year. In summary, our results lend further credence to the notion that iron overload prior to transplant is detrimental and suggest iron overload may predispose to a higher rate of lethal infections

Designing Genome-Wide Association Studies: Sample Size, Power, Imputation, and the Choice of Genotyping Chip

Genome-wide association studies are revolutionizing the search for the genes underlying human complex diseases. The main decisions to be made at the design stage of these studies are the choice of the commercial genotyping chip to be used and the numbers of case and control samples to be genotyped. The most common method of comparing different chips is using a measure of coverage, but this fails to properly account for the effects of sample size, the genetic model of the disease, and linkage disequilibrium between SNPs. In this paper, we argue that the statistical power to detect a causative variant should be the major criterion in study design. Because of the complicated pattern of linkage disequilibrium (LD) in the human genome, power cannot be calculated analytically and must instead be assessed by simulation. We describe in detail a method of simulating case-control samples at a set of linked SNPs that replicates the patterns of LD in human populations, and we used it to assess power for a comprehensive set of available genotyping chips. Our results allow us to compare the performance of the chips to detect variants with different effect sizes and allele frequencies, look at how power changes with sample size in different populations or when using multi-marker tags and genotype imputation approaches, and how performance compares to a hypothetical chip that contains every SNP in HapMap. A main conclusion of this study is that marked differences in genome coverage may not translate into appreciable differences in power and that, when taking budgetary considerations into account, the most powerful design may not always correspond to the chip with the highest coverage. We also show that genotype imputation can be used to boost the power of many chips up to the level obtained from a hypothetical “complete” chip containing all the SNPs in HapMap. Our results have been encapsulated into an R software package that allows users to design future association studies and our methods provide a framework with which new chip sets can be evaluated

How Accessible Was Information about H1N1 Flu? Literacy Assessments of CDC Guidance Documents for Different Audiences

We assessed the literacy level and readability of online communications about H1N1/09 influenza issued by the Centers for Disease Control and Prevention (CDC) during the first month of outbreak. Documents were classified as targeting one of six audiences ranging in technical expertise. Flesch-Kincaid (FK) measure assessed literacy level for each group of documents. ANOVA models tested for differences in FK scores across target audiences and over time. Readability was assessed for documents targeting non-technical audiences using the Suitability Assessment of Materials (SAM). Overall, there was a main-effect by audience, F(5, 82) = 29.72, P<.001, but FK scores did not vary over time, F(2, 82) = .34, P>.05. A time-by-audience interaction was significant, F(10, 82) = 2.11, P<.05. Documents targeting non-technical audiences were found to be text-heavy and densely-formatted. The vocabulary and writing style were found to adequately reflect audience needs. The reading level of CDC guidance documents about H1N1/09 influenza varied appropriately according to the intended audience; sub-optimal formatting and layout may have rendered some text difficult to comprehend

Changes in Whole Blood Gene Expression in Obese Subjects with Type 2 Diabetes Following Bariatric Surgery: a Pilot Study

A pilot study was performed in order to investigate the effects of bariatric surgery on whole blood gene expression profiles in obese subjects with type 2 diabetes.Whole blood from eleven obese subjects with type 2 diabetes was collected in PAXgene tubes prior to and 6-12 months after bariatric surgery. Total RNA was isolated, amplified, labeled and hybridized to Illumina gene expression microarrays. Clinical and expression data were analyzed using a paired t-test, and correlations between changes in clinical trait and transcript levels were calculated. Pathways were identified using Ingenuity Pathway Analysis and DAVID gene ontology software. Overall, bariatric surgery resulted in significant reduction of body mass index, fasting plasma glucose, fasting plasma insulin, and normalization of glycosylated hemoglobin levels. The expression levels of 204 transcripts, representing 200 unique genes, were significantly altered after bariatric surgery. Among the significantly regulated genes were GGT1, CAMP, DEFA1, LCN2, TP53, PDSS1, OLR1, CNTNAP5, DHCR24, HHAT and SARDH, which have been previously implicated in lipid metabolism, obesity and/or type 2 diabetes. Selected findings were replicated by quantitative real-time-PCR. The changes in expression of seven transcripts, WDR35, FLF45244, DHCR24, TIGD7, TOPBP1, TSHZ1, and FAM8A1 were strongly correlated with the changes in body weight, fasting plasma glucose and glycosylated hemoglobin content. The top pathways associated with gene expression changes after bariatric surgery was lipid metabolism, small molecule biochemistry and gene expression. Two antimicrobial peptides were among the transcripts with the largest changes in gene expression after bariatric surgery.Data from this pilot study suggest that whole blood expression levels of specific transcripts may be useful as biomarkers associated with susceptibility for type 2 diabetes and/or therapeutic response

Associations of β-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort

OBJECTIVE: To quantify the independent and interactive associations of amyloid-β (Aβ) and white matter hyperintensity volume (WMHV) - a marker of presumed cerebrovascular disease (CVD) - with rates of neurodegeneration, and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British birth cohort. METHODS: Participants underwent brain MRI and florbetapir-Aβ positron emission tomography as part of Insight 46, an observational population-based study. Changes in whole brain, ventricular and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI using the Boundary Shift Integral. Linear regression was used to test associations with: baseline Aβ deposition; baseline WMHV; APOE ε4; and office-based Framingham heart study-cardiovascular risk scores (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53 and 69 years. RESULTS: 346 cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time-points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87 ml/year faster whole brain atrophy (95% CI 0.03, 1.72), 0.39 ml/year greater ventricular expansion (95% CI 0.16, 0.64) and 0.016 ml/year faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10 ml additional WMHV at baseline was associated with 1.07 ml/year faster whole brain atrophy (95% CI 0.47, 1.67), 0.31 ml/year greater ventricular expansion (95% CI 0.13, 0.60) and 0.014 ml/year faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjusting for Aβ status and WMHV, and no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, nor any evidence that they acted synergistically with Aβ. CONCLUSIONS: Aβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways

Neuroimaging, clinical and life course correlates of normal-appearing white matter integrity in 70-year-olds

We investigate associations between normal-appearing white matter (NAWM) microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 Birth cohort) underwent PET-MRI around age 70. Mean standardized NAWM integrity metrics (fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI) and orientation dispersion index (ODI)) were derived from diffusion MRI. Linear regression was used to test associations between NAWM metrics and (1) concurrent measures, including whole brain volume, white matter hyperintensity volume (WMHV), PET amyloid and cognition; (2) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socioeconomic position, and genetic risk for Alzheimer’s Disease (APOE-ε4); (3) systolic and diastolic blood pressure and cardiovascular health (FHS-CVS) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). 362 participants met inclusion criteria (mean age 70 years, 49% female). Higher WMHV was associated with lower FA (b=-0.09 [95%CI:-0.11, -0.06] p&amp;lt;0.01), NDI (b=-0.17 [-0.22, -0.12] p&amp;lt;0.01), and higher MD (b=0.14 [-0.10, -0.17] p&amp;lt;0.01); amyloid (in men) was associated with lower FA (b=-0.04 [-0.08, -0.01] p=0.03) and higher MD (b=0.06 [0.01,0.11] p=0.02). FHS-CVS in later-life (age 69) was associated with NAWM [lower FA (b=-0.06 [-0.09, -0.02] p&amp;lt;0.01), NDI (b=-0.10 [-0.17, -0.03] p&amp;lt;0.01), and higher MD (b=0.09 [0.04,0.14] p&amp;lt;0.01). Significant sex interactions (p&amp;lt;0.05) emerged for midlife cardiovascular health (age 53) and NAWM at 70: marginal effect plots demonstrated, in women only, NAWM was associated with higher midlife FHS-CVS (lower FA and NDI), midlife systolic (lower FA, NDI, and higher MD), and diastolic (lower FA and NDI) blood pressure, and greater blood pressure change between 43 and 53 years (lower FA and NDI), independently of WMHV. In summary, poorer NAWM microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how NAWM can provide additional information to overt white matter disease. Our findings further show that greater midlife cardiovascular risk and higher blood pressure were associated with poorer NAWM microstructural integrity in females only, suggesting that women’s brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health

Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: A joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE)

Atrial fibrillation (AF) is a major public health problem1 with global prevalence rates (per 1000000 population) in 2010 being 596.2 (95% uncertainty interval (UI), 558.4-636.7) in men and 373.1 (95% UI, 347.9-402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2-95.4) in men and 59.5 (95% UI, 49.9-74.9) in women.2 Worldwide, AF in association with valvular heart disease (VHD) is also common, and management strategies for this group of patients have been less addressed by randomized trials. The latter have largely focused on 'non-valvular AF' patients leading to major uncertainties over how to define (and treat) such patients. There is also an important heterogeneity in the definition of valvular and non-valvular AF.3 Some physicians assume that any valve disease should be considered as 'valvular' AF. Others consider that only mechanical valve prosthesis and rheumatic mitral stenosis should be defined as 'valvular' AF. The term valvular AF has been arbitrarily applied and the 2016 ESC guidelines have avoided the term 'valvular AF' and refer simply to 'AF related to hemodynamically significant mitral stenosis or prosthetic mechanical heart valves'.4 AF clearly leads to an incremental risk for thromboembolism in patients with mitral valve stenosis, but there are limited data for other valvular diseases. Another proposal is to use the acronym MARM-AF as a simple acronym to designate 'Mechanical and Rheumatic Mitral AF' as an alternative to term 'valvular AF' to designate the clinical scenarios for which at the non-vitamin K antagonist oral anticoagulants (NOACs) are not indicated.5 For this document we recognize the uncertainty in terminology, and our scope largely relates to AF related to 'hemodynamically significant' rheumatic VHD (ie. severe enough to impact on patient's survival or necessitates an intervention or surgery) or prosthetic mechanical heart valves. Nonetheless, thrombo-embolic (TE) risk varies according to valve lesion and may be associated with CHA2DS2VASc score risk factor components, rather than the valve disease per se being causal.6,7 TE risk may also be influenced not only by type but also the severity of the lesion. For example, the degree of mitral regurgitation may matter when it comes to risk of TE as some studies suggest that mild (Grade 1) mitral regurgitation is associated with a 2.7-fold increased risk of stroke/TE, while severe forms may possibly have a 'protective' effect (HR = 0.45 for stroke and 0.27 for LA stasis.8 An appropriate definition of 'valvular AF' would need to identify a subgroup of patients with similar pathophysiology of thrombo-embolism, TE risk, and treatment strategies6,9; however, this would be challenging given the major heterogeneity of the condition. This consensus document proposes that the term 'valvular AF' is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional EHRA (EvaluatedHeartvalves, Rheumatic orArtificial) categorization in relation to the type of OAC use in patients with AF, as follows:Evaluated Heartvalves, Rheumatic or Artificial (EHRA) Type 1,which refers to AF patients with 'VHD needing therapy with a Vitamin K antagonist (VKA)

Assessment of Local Public Health Workers' Willingness to Respond to Pandemic Influenza through Application of the Extended Parallel Process Model

Local public health agencies play a central role in response to an influenza pandemic, and understanding the willingness of their employees to report to work is therefore a critically relevant concern for pandemic influenza planning efforts. Witte's Extended Parallel Process Model (EPPM) has been found useful for understanding adaptive behavior in the face of unknown risk, and thus offers a framework for examining scenario-specific willingness to respond among local public health workers. We thus aim to use the EPPM as a lens for examining the influences of perceived threat and efficacy on local public health workers' response willingness to pandemic influenza.We administered an online, EPPM-based survey about attitudes/beliefs toward emergency response (Johns Hopkins approximately Public Health Infrastructure Response Survey Tool), to local public health employees in three states between November 2006-December 2007. A total of 1835 responses were collected for an overall response rate of 83%. With some regional variation, overall 16% of the workers in 2006-7 were not willing to "respond to a pandemic flu emergency regardless of its severity". Local health department employees with a perception of high threat and high efficacy--i.e., those fitting a 'concerned and confident' profile in the EPPM analysis--had the highest declared rates of willingness to respond to an influenza pandemic if required by their agency, which was 31.7 times higher than those fitting a 'low threat/low efficacy' EPPM profile.In the context of pandemic influenza planning, the EPPM provides a useful framework to inform nuanced understanding of baseline levels of--and gaps in--local public health workers' response willingness. Within local health departments, 'concerned and confident' employees are most likely to be willing to respond. This finding may allow public health agencies to design, implement, and evaluate training programs focused on emergency response attitudes in health departments

High-Resolution Mapping of Expression-QTLs Yields Insight into Human Gene Regulation

Recent studies of the HapMap lymphoblastoid cell lines have identified large numbers of quantitative trait loci for gene expression (eQTLs). Reanalyzing these data using a novel Bayesian hierarchical model, we were able to create a surprisingly high-resolution map of the typical locations of sites that affect mRNA levels in cis. Strikingly, we found a strong enrichment of eQTLs in the 250 bp just upstream of the transcription end site (TES), in addition to an enrichment around the transcription start site (TSS). Most eQTLs lie either within genes or close to genes; for example, we estimate that only 5% of eQTLs lie more than 20 kb upstream of the TSS. After controlling for position effects, SNPs in exons are ∼2-fold more likely than SNPs in introns to be eQTLs. Our results suggest an important role for mRNA stability in determining steady-state mRNA levels, and highlight the potential of eQTL mapping as a high-resolution tool for studying the determinants of gene regulation