Cost-Effectiveness of Selective Laser Trabeculoplasty (SLT) versus Argon Laser Trabeculoplasty (ALT) in Uncontrolled Open Angle Glaucoma Patients having at least One Full Previous SLT: An Economic Evaluation Alongside an Ongoing Randomized Controlled Clinical Trial

Background and objective: ALT and SLT are both safe and effective for glaucoma treatment. We performed a cost-effectiveness analysis (CEA) of SLT versus ALT for a six-month follow-up period in uncontrolled open angle glaucoma patients having at least one full previous SLT from an ongoing RCT. Methods: Trial based treatment costing and IOP reduction at 6-month follow-up from baseline for both intervention arms were calculated. A decision tree model was developed considering possible clinical pathways of patients undergoing repeat laser trabeculoplasty. CEA among ALT and SLT was done, and ICERs were calculated from both societal and ministry perspective. One way sensitivity analysis was done for cost and effectiveness parameters. Results: From Societal perspective, expected cost/effectiveness for ALT and SLT was $458/0.143 mmHg vs$448/0.123 mmHg respectively and from ministry perspective, $467/0.154 mmHg vs$446/0.122 mmHg, respectively. To switch from SLT to ALT, it would cost $356.49 for each extra unit IOP reduction from societal perspective and from ministry perspective, the same would cost$ 649.71. This ICERs were much higher in comparison to ICERS of other IOP lowering medications in similar situations. Conclusion: Neither ALT nor SLT strategies were clearly dominated by any other. ALT is slightly more effective and slightly costly over SLT. Sensitivity analysis with effectiveness variables showed dominance of SLT over ALT for some instances. SLT has the theoretical plausibility of repeatability and is also easier to perform than ALT. All these factors should be considered when opting between ALT and SLT strategies

Interpretation of genome-wide infinium methylation data from ligated DNA in formalin-fixed, paraffin-embedded paired tumor and normal tissue

<p>Abstract</p> <p>Background</p> <p>Formalin-fixed, paraffin-embedded (FFPE) samples are a highly desirable resource for epigenetic studies, but there is no suitable platform to assay genome-wide methylation in these widely available resources. Recently, Thirlwell et al. (2010) have reported a modified ligation-based DNA repair protocol to prepare FFPE DNA for the Infinium methylation assay. In this study, we have tested the accuracy of methylation data obtained with this modification by comparing paired fresh-frozen (FF) and FFPE colon tissue (normal and tumor) from colorectal cancer patients. We report locus-specific correlation and concordance of tumor-specific differentially methylated loci (DML), both of which were not previously assessed.</p> <p>Methods</p> <p>We used Illumina's Infinium Methylation 27K chip for 12 pairs of FF and 12 pairs of FFPE tissue from tumor and surrounding healthy tissue from the resected colon of the same individual, after repairing the FFPE DNA using Thirlwell's modified protocol.</p> <p>Results</p> <p>For both tumor and normal tissue, overall correlation of β values between all loci in paired FF and FFPE was comparable to previous studies. Tissue storage type (FF or FFPE) was found to be the most significant source of variation rather than tissue type (normal or tumor). We found a large number of DML between FF and FFPE DNA. Using ANOVA, we also identified DML in tumor compared to normal tissue in both FF and FFPE samples, and out of the top 50 loci in both groups only 7 were common, indicating poor concordance. Likewise, while looking at the correlation of individual loci between FFPE and FF across the patients, less than 10% of loci showed strong correlation (r ≥ 0.6). Finally, we checked the effect of the ligation-based modification on the Infinium chemistry for SNP genotyping on an independent set of samples, which also showed poor performance.</p> <p>Conclusion</p> <p>Ligation of FFPE DNA prior to the Infinium genome-wide methylation assay may detect a reasonable number of loci, but the numbers of detected loci are much fewer than in FF samples. More importantly, the concordance of DML detected between FF and FFPE DNA is suboptimal, and DML from FFPE tissues should be interpreted with great caution.</p

A Prospective Study of Tobacco Smoking and Mortality in Bangladesh

Background: Limited data are available on smoking-related mortality in low-income countries, where both chronic disease burden and prevalence of smoking are increasing.Methods: Using data on 20, 033 individuals in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, we prospectively evaluated the association between tobacco smoking and all-cause, cancer, and cardiovascular disease mortality during ∼7.6 years of follow-up.Cox proportional hazards models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for deaths from all-cause, cancer, CVD, ischemic heart disease (IHD), and stroke, in relation to status, duration, and intensity of cigarette/bidi and hookah smoking.Results: Among men, cigarette/bidi smoking was positively associated with all-cause (HR 1.40, 95% CI 1.06 1.86) and cancer mortality (HR 2.91, 1.24 6.80), and there was a dose-response relationship between increasing intensity of cigarette/bidi consumption and increasing mortality. An elevated risk of death from ischemic heart disease (HR 1.87, 1.08 3.24) was associated with current cigarette/bidi smoking. Among women, the corresponding HRs were 1.65 (95% CI 1.16 2.36) for all-cause mortality and 2.69 (95% CI 1.20 6.01) for ischemic heart disease mortality. Similar associations were observed for hookah smoking. There was a trend towards reduced risk for the mortality outcomes with older age at onset of cigarette/bidi smoking and increasing years since quitting cigarette/bibi smoking among men. We estimated that cigarette/bidi smoking accounted for about 25.0% of deaths in men and 7.6% in women.Conclusions: Tobacco smoking was responsible for substantial proportion of premature deaths in the Bangladeshi population, especially among men. Stringent measures of tobacco control and cessation are needed to reduce tobacco-related deaths in Bangladesh.</p

A RESTful API for Accessing Microbial Community Data for MG-RAST

Many health outcomes are influenced by a person's body mass index, as well as by the trajectory of body mass index through a lifetime. Although previous research has established that body mass index related traits are influenced by genetics, the relationship between these traits and genetics has not been well characterized in people of South Asian ancestry. To begin to characterize this relationship, we analyzed the association between common genetic variation and five phenotypes related to body mass index in a population-based sample of 5,354 Bangladeshi adults. We discovered a significant association between SNV rs347313 (intron of NOS1AP) and change in body mass index in women over two years. In a linear mixed-model, the G allele was associated with an increase of 0.25 kg/m2 in body mass index over two years (p-value of 2.3·10−8). We also estimated the heritability of these phenotypes from our genotype data. We found significant estimates of heritability for all of the body mass index-related phenotypes. Our study evaluated the genetic determinants of body mass index related phenotypes for the first time in South Asians. The results suggest that these phenotypes are heritable and some of this heritability is driven by variation that differs from those previously reported. We also provide evidence that the genetic etiology of body mass index related traits may differ by ancestry, sex, and environment, and consequently that these factors should be considered when assessing the genetic determinants of the risk of body mass index-related disease

A missense variant in <i>FTCD</i> is associated with arsenic metabolism and toxicity phenotypes in Bangladesh

Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity

Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study

Objective To evaluate the association between arsenic exposure and mortality from cardiovascular disease and to assess whether cigarette smoking influences the association

A Prospective Study of Arsenic Exposure, Arsenic Methylation Capacity, and Risk of Cardiovascular Disease in Bangladesh

Millions of persons worldwide, including 13 million Americans (U.S. Environmental Protection Agency 2009) and over 50 million in Bangladesh (British Geological Survey 2007), have been chronically exposed to arsenic, a group 1 human carcinogen (International Agency for Research on Cancer 2004), through contaminated drinking water. Arsenic exposure from drinking water has been associated with cardiovascular disease (CVD) (Chen CJ et al. 1996; Chen Y et al. 2011; Chiou et al. 1997; Liao et al. 2012; Tseng et al. 2003; Yuan et al. 2007). However, prospective studies assessing susceptibility to CVD due to arsenic exposure are rare. Arsenic in drinking water is present as inorganic arsenic (iAS). Once ingested, iAs is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). The relative distribution of urinary arsenic metabolites varies from person to person and has been interpreted to reflect arsenic methylation capacity (Hopenhayn-Rich et al. 1996; Vahter 1999). Mechanistic studies have shown that MMAIII is more toxic than iAs or any of the pentavalent metabolites (Petrick et al. 2000; Styblo et al. 2000). Incomplete methylation, indicated by a high percentage of urinary MMA (MMA%), has been consistently related to cancers (Chen YC et al. 2003; Pu et al. 2007; Steinmaus et al. 2006; Yu et al. 2000), and there is some evidence of stronger associations among smokers than nonsmokers (Pu et al. 2007; Steinmaus et al. 2006). However, the association between urinary MMA% and CVD risk is unknown, and research on the combined effects of arsenic and biomarkers of arsenic susceptibility on CVD risk is needed. We conducted a prospective case–cohort study nested in a large prospective cohort to assess associations of arsenic exposure from drinking water and arsenic methylation capacity, indicated using relative distribution of urinary arsenic metabolites, with CVD risk

Arsenic and Lung Disease Mortality in Bangladeshi Adults

Chronic arsenic exposure through drinking water is a public health problem affecting millions of people worldwide, including at least 30 million in Bangladesh. We prospectively investigated the associations of arsenic exposure and arsenical skin lesion status with lung disease mortality in Bangladeshi adults

Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

Background: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity