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Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations. [ABSTRACT FROM AUTHOR]

Uncontrolled fires place considerable burdens on forest ecosystems, compromising our ability to meet conservation and restoration goals. A poor understanding of the impacts of fire on ecosystems and their biodiversity exacerbates this challenge, particularly in tropical regions where few studies have applied consistent analytical techniques to examine a broad range of ecological impacts over multiyear time frames. We compiled 16 y of data on ecosystem properties (17 variables) and biodiversity (21 variables) from a tropical peatland in Indonesia to assess fire impacts and infer the potential for recovery. Burned forest experienced altered structural and microclimatic conditions, resulting in a proliferation of nonforest vegetation and erosion of forest ecosystem properties and biodiversity. Compared to unburned forest, habitat structure, tree density, and canopy cover deteriorated by 58 to 98%, while declines in species diversity and abundance were most pronounced for trees, damselflies, and butterflies, particularly for forest specialist species. Tracking ecosystem property and biodiversity datasets over time revealed most to be sensitive to recurrent high-intensity fires within the wider landscape. These megafires immediately compromised water quality and tree reproductive phenology, crashing commercially valuable fish populations within 3 mo and driving a gradual decline in threatened vertebrates over 9 mo. Burned forest remained structurally compromised long after a burn event, but vegetation showed some signs of recovery over a 12-y period. Our findings demonstrate that, if left uncontrolled, fire may be a pervasive threat to the ecological functioning of tropical forests, underscoring the importance of fire prevention and long-term restoration efforts, as exemplified in Indonesia., Competing Interests: Competing interests statement:The authors declare no competing interest.

Flocculated suspended sediments (flocs) are found in a variety of environments globally, and their transport and behavior bear substantial importance to several industries including fisheries, aquaculture, and shipping. Additionally, the modelling of their behavior is important for estuarine and coastal flood prediction and defence, and the process of flocculation occurs in other unrelated industries such as paper and chemical production. Floc porosity is conventionally assessed using inferential indirect or proxy data approaches. These methods underestimate floc porosity % by c. 30% and cannot measure the micro-scale complexity of these pore spaces and networks, rendering inputs to models sub-optimal. This study introduces a novel 3D porosity and pore space quantification protocol, that produces directly quantified porosity % and pore space data.•3D floc data from micro-CT scanning is segmented volumetrically•This segmented volume is quantified to extract porosity and several pore space parameters from the floc structure., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Natural sediment flocs are fragile, highly irregular, loosely bound aggregates comprising minerogenic and organic material. They contribute a major component of suspended sediment load and are critical for the fate and flux of sediment, carbon and pollutants in aquatic environments. Understanding their behaviour is essential to the sustainable management of waterways, fisheries and marine industries. For several decades, modelling approaches have utilised fractal mathematics and observations of two dimensional (2D) floc size distributions to infer levels of aggregation and predict their behaviour. Whilst this is a computationally simple solution, it is highly unlikely to reflect the complexity of natural sediment flocs and current models predicting fine sediment hydrodynamics are not efficient. Here, we show how new observations of fragile floc structures in three dimensions (3D) demonstrate unequivocally that natural flocs are non-fractal. We propose that floc hierarchy is based on observations of 3D structure and function rather than 2D size distribution. In contrast to fractal theory, our data indicate that flocs possess characteristics of emergent systems including non-linearity and scale-dependent feedbacks. These concepts and new data to quantify floc structures offer the opportunity to explore new emergence-based floc frameworks which better represent natural floc behaviour and could advance our predictive capacity.

Historical mining activities cause widespread, long-term trace metal contamination of freshwater ecosystems. However, measuring trace metal bioavailability has proven difficult, because it depends on many factors, not least concentrations in water, sediment and habitat. Simple tools are needed to assess bioavailabilities. The use of biomonitors has been widely advocated to provide a realistic measure. To date there have been few attempts to identify ubiquitous patterns of trace metal accumulation within and between freshwater biomonitors at geographical scales relevant to trace metal contamination. Here we address this through a nationwide collection of freshwater biomonitors (species of Gammarus, Leuctra, Baetis, Rhyacophila, Hydropsyche) from 99 English and Welsh stream sites spanning a gradient of high to low trace metal loading. The study tested for inter-biomonitor variation in trace metal body burden, and for congruence amongst accumulations of trace metals within taxa and between taxa across the gradient. In general, significant differences in trace metal body burden occurred between taxa: Gammarus sp. was the most different compared with insect biomonitors. Bivariate relationships between trace metals within biomonitors reflected trace metal profiles in the environment. Strong correlations between some trace metals suggested accumulation was also influenced by physiological pathways. Bivariate relationships between insect biomonitors for body burdens of As, Cu, Mn and Pb were highly consistent. Our data show that irrespective of taxonomic or ecological differences, there is a commonality of response amongst insect taxa, indicating one or more could provide consistent measures of trace metal bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite growing interest in the environmental impact of microplastics, a standardized characterization method is not available. We carried out a systematic analysis of reliable global data detailing the relative abundance of polymers in freshwaters and estuaries. The polymers were identified according to seven main categories: polyethylene terephthalate, polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyurethane and a final category of miscellaneous plastic. The results show that microplastics comprised of polyvinyl chloride and polyurethane are significantly less abundant than would be expected based on global production, possibly due to their use. This has implications for models of microplastic release into the environment based on production and fate. When analysed by matrix (water, sediment or biota) distinct profiles were obtained for each category. Polyethylene, polypropylene and polystyrene were more abundant in sediment than in biota, while miscellaneous plastics was more frequent in biota. The data suggest that environmental sorting of microplastic particles, influenced by physical, chemical and biological processes, may play a key role in environmental impact, although partitioning among matrices based on density was not realized. The distinct profile of microplastics in biota raises an important question regarding potential selectivity in uptake by organisms, highlighting the priority for more and better-informed laboratory exposure studies.

Background: Stereotactic radiotherapy (SBRT) might improve pain and local control in patients with bone metastases compared to conventional radiotherapy, although an overall estimate of these outcomes is currently unknown., Methods: A systematic review was carried out following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pubmed, Embase, and Cochrane databases were systematically searched to identify studies reporting pain response and local control among patients with bone metastases from solid-organ tumors who underwent SBRT in 1-6 fractions. All studies prior to April 15, 2017, were included. Study quality was assessed by predefined criteria, and pain response and local control rates were extracted., Results: A total of 2619 studies were screened; 57 were included (reporting outcomes for 3995 patients) of which 38 reported pain response and 45 local control rates. Local control rates were high with pain response rates above those previously reported for conventional radiotherapy. Marked heterogeneity in study populations and delivered treatments were identified such that quantitative synthesis was not appropriate. Reported toxicity was limited. Of the pain response studies, 73.7% used a retrospective cohort design and only 10.5% used the international consensus endpoint definitions of pain response. The median survival within the included studies ranged from 8 to 30.4 months, suggesting a high risk of selection bias in the included observational studies., Conclusions: This review demonstrates the potential benefit of SBRT over conventional palliative radiotherapy in improving pain due to bone metastases. Given the methodological limitations of the published literature, however, large randomized trials are now urgently required to better quantify this benefit., (© The Author(s) 2019. Published by Oxford University Press.)

Introduction: Surgery is the standard of care for early-stage lung cancer, with stereotactic ablative body radiotherapy (SABR) a lower morbidity alternative for patients with limited physiological reserve. Comparisons of outcomes between these treatment options are limited by competing comorbidities and differences in pre-treatment pathological information. This study aims to address these issues by assessing both overall and cancer-specific survival for presumed stage I lung cancer on an intention-to-treat basis., Methods: This retrospective intention-to-treat analysis identified all patients treated for presumed stage I lung cancer within a single large UK centre. Overall survival, cancer-specific survival, and combined cancer and treatment-related survival were assessed with adjustment for confounding variables using Cox proportional hazards and Fine-Gray competing risks analyses., Results: 468 patients (including 316 surgery and 99 SABR) were included in the study population. Compared with surgery, SABR was associated with inferior overall survival on multivariable Cox modelling (SABR HR 1.84 (95% CI 1.32-2.57)), but there was no difference in cancer-specific survival (SABR HR 1.47 (95% CI 0.80-2.69)) or combined cancer and treatment-related survival (SABR HR 1.27 (95% CI 0.74-2.17)). Combined cancer and treatment-related death was no different between SABR and surgery on Fine-Gray competing risks multivariable modelling (subdistribution hazard 1.03 (95% CI 0.59-1.81)). Non-cancer-related death was significantly higher in SABR than surgery (subdistribution hazard 2.16 (95% CI 1.41-3.32))., Conclusion: In this analysis, no difference in cancer-specific survival was observed between SABR and surgery. Further work is needed to define predictors of outcome and help inform treatment decisions., Competing Interests: Conflict of interest: K.L. Spencer has nothing to disclose. Conflict of interest: M.P.T. Kennedy has nothing to disclose. Conflict of interest: K.L. Lummis has nothing to disclose. Conflict of interest: D.A.B. Ellames has nothing to disclose. Conflict of interest: M. Snee has nothing to disclose. Conflict of interest: A. Brunelli has nothing to disclose. Conflict of interest: K. Franks reports personal fees for advisory board work from Pfizer and BMS, personal fees for advisory board work and support for conference attendance from AstraZeneca, and personal fees for educational meetings and support for conference attendance from Boehringer Ingelheim, outside the submitted work. Conflict of interest: M.E.J. Callister has nothing to disclose., (Copyright ©ERS 2019.)

Purpose: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci., Methods: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study., Results: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05×10(-8) and P=6.36×10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing., Conclusions: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Background: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S., Methods: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites., Results: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only., Conclusions: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging., Competing Interests: The authors have declared that no competing interests exist. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, the Centers for Disease Control, the Indian Health Service, or any other funding agency.

Study Question: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?, Summary Answer: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry., What Is Known Already: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations., Study Design, Size, Duration: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM., Materials, Setting, Methods: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses., Main Results and the Role of Chance: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends., Limitations, Reasons for Caution: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings., Wider Implications of the Findings: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

Genetic association studies have rapidly become a major tool for identifying the genetic basis of common human diseases. The advent of cost-effective genotyping coupled with large collections of samples linked to clinical outcomes and quantitative traits now make it possible to systematically characterize genotype-phenotype relationships in diverse populations and extensive datasets. To capitalize on these advancements, the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) project, as part of the collaborative Population Architecture using Genomics and Epidemiology (PAGE) study, accesses two collections: the National Health and Nutrition Examination Surveys (NHANES) and BioVU, Vanderbilt University's biorepository linked to de-identified electronic medical records. We describe herein the workflows for accessing and using the epidemiologic (NHANES) and clinical (BioVU) collections, where each workflow has been customized to reflect the content and data access limitations of each respective source. We also describe the process by which these data are generated, standardized, and shared for meta-analysis among the PAGE study sites. As a specific example of the use of BioVU, we describe the data mining efforts to define cases and controls for genetic association studies of common cancers in PAGE. Collectively, the efforts described here are a generalized outline for many of the successful approaches that can be used in the era of high-throughput genotype-phenotype associations for moving biomedical discovery forward to new frontiers of data generation and analysis.

Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p = 5×10⁻⁰⁸; KCNQ1 rs79972789, p = 1.9×10⁻⁰⁷; COL4A3BP rs181686584, p = 2.9×10⁻⁰⁷). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6×10⁻⁰⁶). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.

Purpose: Age-related macular degeneration (AMD) is a complex disorder of the retina, characterized by drusen, geographic atrophy, and choroidal neovascularization. Cigarette smoking and the genetic variants CFH Y402H, ARMS2 A69S, CFB R32Q, and C3 R102G have been strongly and consistently associated with AMD. Multiple linkage studies have found evidence suggestive of another AMD locus on chromosome 16p12 but the gene responsible has yet to be identified., Methods: In the initial phase of the study, single-nucleotide polymorphisms (SNPs) across chromosome 16 were examined for linkage and/or association in 575 Caucasian individuals from 148 multiplex and 77 singleton families. Additional variants were tested in an independent dataset of unrelated cases and controls. According to these results, in combination with gene expression data and biological knowledge, five genes were selected for further study: CACNG3, HS3ST4, IL4R, Q7Z6F8, and ITGAM., Results: After genotyping additional tagging SNPs across each gene, the strongest evidence for linkage and association was found within CACNG3 (rs757200 nonparametric LOD* = 3.3, APL (association in the presence of linkage) P = 0.06, and rs2238498 MQLS (modified quasi-likelihood score) P = 0.006 in the families; rs2283550 P = 1.3 × 10(-6), and rs4787924 P = 0.002 in the case-control dataset). After adjusting for known AMD risk factors, rs2283550 remained strongly associated (P = 2.4 × 10(-4)). Furthermore, the association signal at rs4787924 was replicated in an independent dataset (P = 0.035) and in a joint analysis of all the data (P = 0.001)., Conclusions: These results suggest that CACNG3 is the best candidate for an AMD risk gene within the 16p12 linkage peak. More studies are needed to confirm this association and clarify the role of the gene in AMD pathogenesis.

A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy.

Controversy remains as to which gene at the chromosome 10q26 locus confers risk for age-related macular degeneration (AMD) and statistical genetic analysis is confounded by the strong linkage disequilibrium (LD) across the region. Functional analysis of related genetic variations could solve this puzzle. Recently, Fritsche et al. reported that AMD is associated with unstable ARMS2 transcripts possibly caused by a complex insertion/deletion (indel; consisting of a 443 bp deletion and an adjacent 54 bp insertion) in its 3'UTR (untranslated region). To validate this indel, we sequenced our samples. We found that this indel is even more complex and is composed of two side-by-side indels separated by 17 bp: (1) 9 bp deletion with 10 bp insertion; (2) 417 bp deletion with 27 bp insertion. The indel is significantly associated with the risk of AMD, but is also in strong LD with the non-synonymous single nucleotide polymorphism rs10490924 (A69S). We also found that ARMS2 is expressed not only in placenta and retina but also in multiple human tissues. Using quantitative PCR, we found no correlation between the indel and ARMS2 mRNA level in human retina and blood samples. The lack of functional effects of the 3'UTR indel, the amino acid substitution of rs10490924 (A69S), and strong LD between them suggest that A69S, not the indel, is the variant that confers risk of AMD. To our knowledge, it is the first time it has been shown that ARMS2 is widely expressed in human tissues. Conclusively, the indel at 3'UTR of ARMS2 actually contains two side-by-side indels. The indels are associated with risk of AMD, but not correlated with ARMS2 mRNA level.

Principal components analysis (PCA) is a multivariate statistical technique capable of discerning patterns in large environmental datasets. Although widely used, there is disparity in the literature with respect to data pre-treatment prior to PCA. This research examines the influence of commonly reported data pre-treatment methods on PCA outputs, and hence data interpretation, using a typical environmental dataset comprising sediment geochemical data from an estuary in SE England. This study demonstrated that applying the routinely used log (x + 1) transformation skewed the data and masked important trends. Removing outlying samples and correcting for the influence of grain size had the most significant effect on PCA outputs and data interpretation. Reducing the influence of grain size using granulometric normalisation meant that other factors affecting metal variability, including mineralogy, anthropogenic sources and distance along the salinity transect could be identified and interpreted more clearly.

Purpose: To analyze the relationship between ARMS2 and HTRA1 in the association with age-related macular degeneration (AMD) in an independent case-control dataset and to investigate the subcellular localization of the ARMS2 protein in an in vitro system., Methods: Two SNPs in ARMS2 and HTRA1 were genotyped in 685 cases and 269 controls by a genotyping assay. Allelic association was tested by a chi(2) test. A likelihood ratio test (LRT) of full versus reduced models was used to analyze the interaction between ARMS2 and smoking and HTRA1 and smoking, after adjustment for CFH and age. Immunofluorescence and immunoblot were applied to localize ARMS2 in retinal epithelial ARPE-19 cells and COS7 cell transfected by ARMS2 constructs., Results: Both significantly associated SNP rs10490924 and rs11200638 (P < 0.0001) are in strong linkage disequilibrium (LD; D' = 0.97, r(2) = 0.93) that generates virtually identical association test and odds ratios. In separate logistic regression models, the interaction effect for both smoking with ARMS2 and with HTRA1 was not statistically significant. Immunofluorescence and immunoblot show that both endogenous and exogenous ARMS2 are mainly distributed in the cytosol, not the mitochondria. Compared with the wild-type, ARMS2 A69S is more likely to be associated with the cytoskeleton in COS7 cells., Conclusions: The significant associations in ARMS2 and HTRA1 are with polymorphisms in strong LD that confer virtually identical risks, preventing differentiation at the statistical level. ARMS2 was mainly distributed in the cytosol, not in the mitochondrial outer membrane as previously reported, suggesting that ARMS2 may not confer risk to AMD through the mitochondrial pathway.

Purpose: Age-related macular degeneration (AMD) is a devastating disorder that adversely affects the quality of life of nearly 2 million Americans who have advanced forms of the disease. Besides the well-known risk imparted by carrying the Y402H variant in the complement factor H (CFH) gene on chromosome 1, recent evidence of the existence of protective haplotypes spanning CFH has been reported., Methods: The haplo.stats program was used to test for association of the protective haplotypes after adjusting for age in the dataset of 584 sporadic cases and 248 control samples. Logistic regression modeling and likelihood ratio tests were used to investigate an interaction between a particular haplotype and smoking status. The HBAT option of FBAT was used to confirm the associations in an independent dataset of 201 families., Results: Two protective (P) haplotypes in a family-based dataset (P1 = CAATTTAG, P = 0.021; and P2 = CGGCTTAG, P = 0.018) were identified for the first time. Age-adjusted score statistics provided support for these protective haplotypes in the case-control dataset (P1 frequency in cases approximately 13%, in controls approximately 20%, P = 0.001; P2 frequency in cases approximately 5%, in controls approximately 8%, P = 0.077). There was also tentative evidence of an interaction between one of the protective haplotypes and cigarette smoking (P = 0.04 likelihood ratio test for P2-smoking interaction)., Conclusions: Replication of the association between the protective haplotypes and decreased AMD susceptibility provides increased evidence that these associations have biological meaning. The suggestion of a haplotype-smoking interaction adds to the growing body of evidence that smoking is an important environmental covariate in AMD that should be considered in genetic studies. Identification of the protective variant(s) carried within these haplotypes is critical for understanding the etiology of AMD.

The use of water injection dredging (WID) is increasing in the UK's inland waterways and marinas. Jets of water are injected under low pressure directly into bottom sediment creating a turbulent water-sediment mixture that flows under the influence of gravity. Many of these sediments are highly contaminated and little is known of the effects of contaminant release on water quality or the risk to biota living in both the sediment and the water column. Sediment cores were collected from Limehouse Basin, a proposed WID site in SE England and current sediment toxicity was assessed using a number of techniques. Comparison of metal data to US sediment quality guidelines indicated intermediate levels of toxicity while, calculation of acid volatile sulphide to simultaneously extracted metal ratios underestimated the potential toxicity to sediment dwelling organisms. In contrast, porewater ammonia concentrations were in excess of all published ecotoxicological guidelines and indicate serious risk to biota. Re-suspension experiments were used to mimic the effects of WID on overlying water quality and ecotoxicity tests were carried out on elutriates using Daphnia magna to examine the impacts on biota. Concentrations of a range of metals in the elutriates predict that adverse biological effects would be observed during WID, however only 10% of the elutriate samples caused an adverse effect on Daphnia. Limehouse Basin is a complex aquatic environment receiving predominantly fresh waters while the sediments have high porewater chloride concentrations reminiscent of previous tidal inputs to the basin, making the choice of test organism problematic.

If snow cover in alpine environments were reduced through climatic warming, plants that are normally protected by snow-lie in winter would become exposed to greater extremes of temperature and solar radiation. We examined the annual course of frost resistance of species of native alpine plants from southern New Zealand that are normally buried in snowbanks over winter (Celmisia haastii and Celmisia prorepens) or in sheltered areas that may accumulate snow (Hebe odora) and other species, typical of more exposed areas, that are relatively snow-free (Celmisia viscosa, Poa colensoi, Dracophyllum muscoides). The frost resistance of these principal species was in accord with habitat: those from snowbanks or sheltered areas showed the least frost resistance, whereas species from exposed areas had greater frost resistance throughout the year. P. colensoi had the greatest frost resistance (-32.5 degrees C). All the principal species showed a rapid increase in frost resistance from summer to early winter (February-June) and maximum frost resistance in winter (July-August). The loss of resistance in late winter to early summer (August-December) was most rapid in P. colensoi and D. muscoides. Seasonal frost resistance of the principal species was more strongly related to daylength than to temperature, although all species except C. viscosa were significantly related to temperature when the influence of daylength was accounted for. Measurements of chlorophyll fluorescence indicated that photosynthetic efficiency of the principal species declined with increasing daylength. Levels of frost resistance of the six principal alpine plant species, and others measured during the growing season, were similar to those measured in tropical alpine areas and somewhat more resistant than those recorded in alpine areas of Europe. The potential for frost damage was greatest in spring. The current relationship of frost resistance with daylength is sufficient to prevent damage at any time of year. While warmer temperatures might lower frost resistance, they would also reduce the incidence of frosts, and the incidence of frost damage is unlikely to be altered. The relationship of frost resistance with daylength and temperature potentially provides a means of predicting the responses of alpine plants in response to global warming.

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in the elderly whose etiology remains largely unknown. Previous studies identified chromosome 1q32 as harboring a susceptibility locus for AMD. We used single-nucleotide polymorphisms to interrogate this region and identified a strongly associated haplotype in two independent data sets. DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant, Y402H, that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57. This common variant likely explains approximately 43% of AMD in older adults.

Clinical chemical determinations were carried out on blood removed by cardiac puncture from 49 mink affected with Aleutian disease and 25 normal animals and the respective differences tested for statistical significance. Blood urea nitrogen, serum total protein and globulin, thymol turbidity, glutamic oxalacetic and glutamic pyruvic transaminases and amylase were definitely elevated in the affected animals whereas serum calcium, albumin and A/G ratio were depressed. No statistically significant difference was apparent between the two groups in the comparison of inorganic phosphorus, alkaline and acid phosphatases, bilirubin, total cholesterol and esters, cephalin-cholesterol flocculation (3+ in each case), sodium, potassium, chloride, CO(2)-combining power, leucine aminopeptidase and lactic dehydrogenase (means: over 2,000 u./ml.). For both the control and affected mink, the distribution of serum lactic dehydrogenase isozymes resembled that of human homologous serum hepatitis. Electrophoresis of serum proteins confirmed earlier findings of hypergammaglobulinemia in the diseased animals but a fast-moving or pre-albumin component, averaging 4% of the total protein, occurred in both the diseased and normal mink.