Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 +/- 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 +/- 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 +/- 0.06 s.e.), and ADHD and major depressive disorder (0.32 +/- 0.07 s.e.), low between schizophrenia and ASD (0.16 +/- 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

A genome-wide association study of sleep habits and insomnia

Several aspects of sleep behavior such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of six sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317, 370, and 610K arrays and the SNPs in common between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the third intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (P = 1.3 x 10(-)(6)). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (P = 0.73). We have identified several other suggestive associations that await replication in an independent sample. We did not replicate the results from previous genome-wide analyses of self-reported sleep phenotypes after correction for multiple testing.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, approximately 0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

Meta-analysis of genome-wide association for migraine in six population-based European cohorts

Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10,980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value<10(-5). The best result was obtained for SNP rs9908234, which had a P-value of 8.00 x 10(-8). This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate.

Harvest strategy evaluations and co-management for the Moreton Bay Trawl Fishery

Non-Technical Summary Seafood CRC Project 2009/774. Harvest strategy evaluations and co-management for the Moreton Bay Trawl Fishery Principal Investigator: Dr Tony Courtney, Principal Fisheries Biologist Fisheries and Aquaculture, Agri-Science Queensland Department of Agriculture, Fisheries and Forestry Level B1, Ecosciences Precinct, Joe Baker St, Dutton Park, Queensland 4102 Email: tony.courtney@daff.qld.gov.au Project objectives: 1. Review the literature and data (i.e., economic, biological and logbook) relevant to the Moreton Bay trawl fishery. 2. Identify and prioritise management objectives for the Moreton Bay trawl fishery, as identified by the trawl fishers. 3. Undertake an economic analysis of Moreton Bay trawl fishery. 4. Quantify long-term changes to fishing power for the Moreton Bay trawl fishery. 5. Assess priority harvest strategies identified in 2 (above). Present results to, and discuss results with, Moreton Bay Seafood Industry Association (MBSIA), fishers and Fisheries Queensland. Note: Additional, specific objectives for 2 (above) were developed by fishers and the MBSIA after commencement of the project. These are presented in detail in section 5 (below). The project was an initiative of the MBSIA, primarily in response to falling profitability in the Moreton Bay prawn trawl fishery. The analyses were undertaken by a consortium of DAFF, CSIRO and University of Queensland researchers. This report adopted the Australian Standard Fish Names (http://www.fishnames.com.au/). Trends in catch and effort The Moreton Bay otter trawl fishery is a multispecies fishery, with the majority of the catch composed of Greasyback Prawns (Metapenaeus bennettae), Brown Tiger Prawns (Penaeus esculentus), Eastern King Prawns (Melicertus plebejus), squid (Uroteuthis spp., Sepioteuthis spp.), Banana Prawns (Fenneropenaeus merguiensis), Endeavour Prawns (Metapenaeus ensis, Metapenaeus endeavouri) and Moreton Bay bugs (Thenus parindicus). Other commercially important byproduct includes blue swimmer crabs (Portunus armatus), three-spot crabs (Portunus sanguinolentus), cuttlefish (Sepia spp.) and mantis shrimp (Oratosquilla spp.). Logbook catch and effort data show that total annual reported catch of prawns from the Moreton Bay otter trawl fishery has declined to 315 t in 2008 from a maximum of 901 t in 1990. The number of active licensed vessels participating in the fishery has also declined from 207 in 1991 to 57 in 2010. Similarly, fishing effort has fallen from a peak of 13,312 boat-days in 1999 to 3817 boat-days in 2008 – a 71% reduction. The declines in catch and effort are largely attributed to reduced profitability in the fishery due to increased operational costs and depressed prawn prices. The low prawn prices appear to be attributed to Australian aquacultured prawns and imported aquacultured vannamei prawns, displacing the markets for trawl-caught prawns, especially small species such as Greasyback Prawns which traditionally dominated landings in Moreton Bay. In recent years, the relatively high Australian dollar has resulted in reduced exports of Australian wild-caught prawns. This has increased supply on the domestic market which has also suppressed price increases. Since 2002, Brown Tiger Prawns have dominated annual reported landings in the Moreton Bay fishery. While total catch and effort in the bay have declined to historically low levels, the annual catch and catch rates of Brown Tiger Prawns have been at record highs in recent years. This appears to be at least partially attributed to the tiger prawn stock having recovered from excessive effort in previous decades. The total annual value of the Moreton Bay trawl fishery catch, including byproduct, is about $5 million, of which Brown Tiger Prawns account for about $2 million. Eastern King Prawns make up about 10% of the catch and are mainly caught in the bay from October to December as they migrate to offshore waters outside the bay where they contribute to a large mono-specific trawl fishery. Some of the Eastern King Prawns harvested in Moreton Bay may be growth overfished (i.e., caught below the size required to maximise yield or value), although the optimum size-at-capture was not determined in this study. Banana Prawns typically make up about 5% of the catch, but can exceed 20%, particularly following heavy rainfall. Economic analysis of the fishery From the economic survey, cash profits were, on average, positive for both fleet segments in both years of the survey. However, after the opportunity cost of capital and depreciation were taken into account, the residual owner-operator income was relatively low, and substantially lower than the average share of revenue paid to employed skippers. Consequently, owner-operators were earning less than their opportunity cost of their labour, suggesting that the fleets were economically unviable in the longer term. The M2 licensed fleet were, on average, earning similar boat cash profits as the T1/M1 fleet, although after the higher capital costs were accounted for the T1/M1 boats were earning substantially lower returns to owner-operator labour. The mean technical efficiency for the fleet as a whole was estimated to be 0.67. That is, on average, the boats were only catching 67 per cent of what was possible given their level of inputs (hours fished and hull units). Almost one-quarter of observations had efficiency scores above 0.8, suggesting a substantial proportion of the fleet are relatively efficient, but some are also relatively inefficient. Both fleets had similar efficiency distributions, with median technical efficiency score of 0.71 and 0.67 for the M2 and T1/M1 boats respectively. These scores are reasonably consistent with other studies of prawn trawl fleets in Australia, although higher average efficiency scores were found in the NSW prawn trawl fleet. From the inefficiency model, several factors were found to significantly influence vessel efficiency. These included the number of years of experience as skipper, the number of generations that the skipper’s family had been fishing and the number of years schooling. Skippers with more schooling were significantly more efficient than skippers with lower levels of schooling, consistent with other studies. Skippers who had been fishing longer were, in fact, less efficient than newer skippers. However, this was mitigated in the case of skippers whose family had been involved in fishing for several generations, consistent with other studies and suggesting that skill was passed through by families over successive generations. Both the linear and log-linear regression models of total fishing effort against the marginal profit per hour performed reasonably well, explaining between 70 and 84 per cent of the variation in fishing effort. As the models had different dependent variables (one logged and the other not logged) this is not a good basis for model choice. A better comparator is the square root of the mean square error (SMSE) expressed as a percentage of the mean total effort. On this criterion, both models performed very similarly. The linear model suggests that each additional dollar of average profits per hour in the fishery increases total effort by around 26 hours each month. From the log linear model, each percentage increase in profits per hour increases total fishing effort by 0.13 per cent. Both models indicate that economic performance is a key driver of fishing effort in the fishery. The effect of removing the boat-replacement policy is to increase individual vessel profitability, catch and effort, but the overall increase in catch is less than that removed by the boats that must exit the fishery. That is, the smaller fleet (in terms of boat numbers) is more profitable but the overall catch is not expected to be greater than before. This assumes, however, that active boats are removed, and that these were also taking an average level of catch. If inactive boats are removed, then catch of the remaining group as a whole could increase by between 14 and 17 per cent depending on the degree to which costs are reduced with the new boats. This is still substantially lower than historical levels of catch by the fleet. Fishing power analyses An analysis of logbook data from 1988 to 2010, and survey information on fishing gear, was performed to estimate the long-term variation in the fleet’s ability to catch prawns (known as fishing power) and to derive abundance estimates of the three most commercially important prawn species (i.e., Brown Tiger, Eastern King and Greasyback Prawns). Generalised linear models were used to explain the variation in catch as a function of effort (i.e., hours fished per day), vessel and gear characteristics, onboard technologies, population abundance and environmental factors. This analysis estimated that fishing power associated with Brown Tiger and Eastern King Prawns increased over the past 20 years by 10–30% and declined by approximately 10% for greasybacks. The density of tiger prawns was estimated to have almost tripled from around 0.5 kg per hectare in 1988 to 1.5 kg/ha in 2010. The density of Eastern King Prawns was estimated to have fluctuated between 1 and 2 kg per hectare over this time period, without any noticeable overall trend, while Greasyback Prawn densities were estimated to have fluctuated between 2 and 6 kg per hectare, also without any distinctive trend. A model of tiger prawn catches was developed to evaluate the impact of fishing on prawn survival rates in Moreton Bay. The model was fitted to logbook data using the maximum-likelihood method to provide estimates of the natural mortality rate (0.038 and 0.062 per week) and catchability (which can be defined as the proportion of the fished population that is removed by one unit of effort, in this case, estimated to be 2.5 ± 0.4 E-04 per boat-day). This approach provided a method for industry and scientists to develop together a realistic model of the dynamics of the fishery. Several aspects need to be developed further to make this model acceptable to industry. Firstly, there is considerable evidence to suggest that temperature influences prawn catchability. This ecological effect should be incorporated before developing meaningful harvest strategies. Secondly, total effort has to be allocated between each species. Such allocation of effort could be included in the model by estimating several catchability coefficients. Nevertheless, the work presented in this report is a stepping stone towards estimating essential fishery parameters and developing representative mathematical models required to evaluate harvest strategies. Developing a method that allowed an effective discussion between industry, management and scientists took longer than anticipated. As a result, harvest strategy evaluations were preliminary and only included the most valuable species in the fishery, Brown Tiger Prawns. Additional analyses and data collection, including information on catch composition from field sampling, migration rates and recruitment, would improve the modelling. Harvest strategy evaluations As the harvest strategy evaluations are preliminary, the following results should not be adopted for management purposes until more thorough evaluations are performed. The effects, of closing the fishery for one calendar month, on the annual catch and value of Brown Tiger Prawns were investigated. Each of the 12 months (i.e., January to December) was evaluated. The results were compared against historical records to determine the magnitude of gain or loss associated with the closure. Uncertainty regarding the trawl selectivity was addressed using two selectivity curves, one with a weight at 50% selection (S50%) of 7 g, based on research data, and a second with S50% of 14 g, put forward by industry. In both cases, it was concluded that any monthly closure after February would not be beneficial to the industry. The magnitude of the benefit of closing the fishery in either January or February was sensitive to which mesh selectivity curve that was assumed, with greater benefit achieved when the smaller selectivity curve (i.e., S50% = 7 g) was assumed. Using the smaller selectivity (S50% = 7 g), the expected increase in catch value was 10–20% which equates to $200,000 to $400,000 annually, while the larger selectivity curve (S50% = 14 g) suggested catch value would be improved by 5–10%, or $100,000 to $200,000. The harvest strategy evaluations showed that greater benefits, in the order of 30–60% increases in the tiger annual catch value, could have been obtained by closing the fishery early in the year when annual effort levels were high (i.e., > 10,000 boat-days). In recent years, as effort levels have declined (i.e., ~4000 boat-days annually), expected benefits from such closures are more modest. In essence, temporal closures offer greater benefit when fishing mortality rates are high. A spatial analysis of Brown Tiger Prawn catch and effort was also undertaken to obtain a better understanding of the prawn population dynamics. This indicated that, to improve profitability of the fishery, fishers could consider closing the fishery in the period from June to October, which is already a period of low profitability. This would protect the Brown Tiger Prawn spawning stock, increase catch rates of all species in the lucrative pre-Christmas period (November–December), and provide fishers with time to do vessel maintenance, arrange markets for the next season’s harvest, and, if they wish, work at other jobs. The analysis found that the instantaneous rate of total mortality (Z) for the March–June period did not vary significantly over the last two decades. As the Brown Tiger Prawn population in Moreton Bay has clearly increased over this time period, an interesting conclusion is that the instantaneous rate of natural mortality (M) must have increased, suggesting that tiger prawn natural mortality may be density-dependent at this time of year. Mortality rates of tiger prawns for June–October were found to have decreased over the last two decades, which has probably had a positive effect on spawning stocks in the October–November spawning period. Abiotic effects on the prawns The influence of air temperature, rainfall, freshwater flow, the southern oscillation index (SOI) and lunar phase on the catch rates of the four main prawn species were investigated. The analyses were based on over 200,000 daily logbook catch records over 23 years (i.e., 1988–2010). Freshwater flow was more influential than rainfall and SOI, and of the various sources of flow, the Brisbane River has the greatest volume and influence on Moreton Bay prawn catches. A number of time-lags were also considered. Flow in the preceding month prior to catch (i.e., 30 days prior, Logflow1_30) and two months prior (31–60 days prior, Logflow31_60) had strong positive effects on Banana Prawn catch rates. Average air temperature in the preceding 4-6 months (Temp121_180) also had a large positive effect on Banana Prawn catch rates. Flow in the month immediately preceding catch (Logflow1_30) had a strong positive influence on Greasyback Prawn catch rates. Air temperature in the preceding two months prior to catch (Temp1_60) had a large positive effect on Brown Tiger Prawn catch rates. No obvious or marked effects were detected for Eastern King Prawns, although interestingly, catch rates declined with increasing air temperature 4–6 months prior to catch. As most Eastern King Prawn catches in Moreton Bay occur in October to December, the results suggest catch rates decline with increasing winter temperatures. In most cases, the prawn catch rates declined with the waxing lunar phase (high luminance/full moon), and increased with the waning moon (low luminance/new moon). The SOI explains little additional variation in prawn catch rates (~ <2%), although its influence was higher for Banana Prawns. Extrapolating findings of the analyses to long-term climate change effects should be interpreted with caution. That said, the results are consistent with likely increases in abundance in the region for the two tropical species, Banana Prawns and Brown Tiger Prawns, as coastal temperatures rise. Conversely, declines in abundance could be expected for the two temperate species, Greasyback and Eastern King Prawns. Corporate management structures An examination of alternative governance systems was requested by the industry at one of the early meetings, particularly systems that may give them greater autonomy in decision making as well as help improve the marketing of their product. Consequently, a review of alternative management systems was undertaken, with a particular focus on the potential for self-management of small fisheries (small in terms of number of participants) and corporate management. The review looks at systems that have been implemented or proposed for other small fisheries internationally, with a particular focus on self-management as well as the potential benefits and challenges for corporate management. This review also highlighted particular opportunities for the Moreton Bay prawn fishery. Corporate management differs from other co-management and even self-management arrangements in that ‘ownership’ of the fishery is devolved to a company in which fishers and government are shareholders. The company manages the fishery as well as coordinates marketing to ensure that the best prices are received and that the catch taken meets the demands of the market. Coordinated harvesting will also result in increased profits, which are returned to fishers in the form of dividends. Corporate management offers many of the potential benefits of an individual quota system without formally implementing such a system. A corporate management model offers an advantage over a self-management model in that it can coordinate both marketing and management to take advantage of this unique geographical advantage. For such a system to be successful, the fishery needs to be relatively small and self- contained. Small in this sense is in terms of number of operators. The Moreton Bay prawn fishery satisfies these key conditions for a successful self-management and potentially corporate management system. The fishery is small both in terms of number of participants and geography. Unlike other fisheries that have progressed down the self-management route, the key market for the product from the Moreton Bay fishery is right at its doorstep. Corporate management also presents a number of challenges. First, it will require changes in the way fishers operate. In particular, the decision on when to fish and what to catch will be taken away from the individual and decided by the collective. Problems will develop if individuals do not join the corporation but continue to fish and market their own product separately. While this may seem an attractive option to fishers who believe they can do better independently, this is likely to be just a short- term advantage with an overall long-run cost to themselves as well as the rest of the industry. There are also a number of other areas that need further consideration, particularly in relation to the allocation of shares, including who should be allocated shares (e.g. just boat owners or also some employed skippers). Similarly, how harvesting activity is to be allocated by the corporation to the fishers. These are largely issues that cannot be answered without substantial consultation with those likely to be affected, and these groups cannot give these issues serious consideration until the point at which they are likely to become a reality. Given the current structure and complexity of the fishery, it is unlikely that such a management structure will be feasible in the short term. However, the fishery is a prime candidate for such a model, and development of such a management structure in the future should be considered as an option for the longer term.

International contact lens prescribing in 2014

Since the late 1990s, the International Contact Lens Prescribing Survey Consortium has prospectively gathered information about 285,000 contact lens fits from more than 50 countries. This article presents our 14th annual summary of current trends published in Contact Lens Spectrum. With only minor differences in the distribution of our surveys among markets, we have continued to adopt the same approach throughout the past 18 years. Through national coordinators, we approach contact lens prescribers in each country and ask them to record information about the first 10 patients whom they fit with contact lenses after receipt of our survey form. The information collected is generic, and respondents are weighted to reflect the volume of contact lens fits undertaken by each. For this 2014 report, we present information about 25,179 contact lens fits from 32 countries...

CattleTickBase: An integrated Internet-based bioinformatics resource for Rhipicephalus (Boophilus) microplus

The Rhipicephalus micro plus genome is large and complex in structure, making it difficult to assemble a genome sequence and costly to resource the required bioinformatics. In light of this, a consortium of international collaborators was formed to pool resources to begin sequencing this genome. We have acquired and assembled genomic DNA into contigs that represent over 1.8 Gigabase pairs of DNA from gene-enriched regions of the R. micro plus genome. We also have several datasets containing transcript sequences from a number of gene expression experiments conducted by the consortium. A web-based resource was developed to enable the scientific community to access our datasets and conduct analysis through a web-based bioinformatics environment called YABI. The collective bioinformatics resource is termed CattleTickBase. Our consortium has acquired genomic and transcriptomic sequence data at approximately 0.9X coverage of the gene-coding regions of the R. microplus genome. The YABI tool will facilitate access and manipulation of cattle tick genome sequence data as the genome sequencing of R. microplus proceeds. During this process the CattleTickBase resource will continue to be updated. Published by Elsevier Ltd. on behalf of Australian Society for Parasitology Inc.

Building local capacity to reduce road traffic injury in rapidly motorising countries

Road safety is a significant public health issue - 1.24m killed each year, 20-50m injured, 91% in rapidly motorising low/mid income countries Decade of Action for Road Safety 2011-2020: - National and local actions: “strengthening the management infrastructure and capacity for technical implementation of road safety activities at the national, regional and global levels” - Capacity as a constraint on a country’s action - Emphasis on knowledge/training – understand principles, promote training and education etc

Systematic review of the psychological consequences of false-positive screening mammograms

- Background In the UK, women aged 50–73 years are invited for screening by mammography every 3 years. In 2009–10, more than 2.24 million women in this age group in England were invited to take part in the programme, of whom 73% attended a screening clinic. Of these, 64,104 women were recalled for assessment. Of those recalled, 81% did not have breast cancer; these women are described as having a false-positive mammogram. - Objective The aim of this systematic review was to identify the psychological impact on women of false-positive screening mammograms and any evidence for the effectiveness of interventions designed to reduce this impact. We were also looking for evidence of effects in subgroups of women. - Data sources MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Health Management Information Consortium, Cochrane Central Register for Controlled Trials, Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination (CRD) Database of Abstracts of Reviews of Effects, CRD Health Technology Assessment (HTA), Cochrane Methodology, Web of Science, Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index-Science, Conference Proceeding Citation Index-Social Science and Humanities, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Sociological Abstracts, the International Bibliography of the Social Sciences, the British Library's Electronic Table of Contents and others. Initial searches were carried out between 8 October 2010 and 25 January 2011. Update searches were carried out on 26 October 2011 and 23 March 2012. - Review methods Based on the inclusion criteria, titles and abstracts were screened independently by two reviewers. Retrieved papers were reviewed and selected using the same independent process. Data were extracted by one reviewer and checked by another. Each included study was assessed for risk of bias. - Results Eleven studies were found from 4423 titles and abstracts. Studies that used disease-specific measures found a negative psychological impact lasting up to 3 years. Distress increased with the level of invasiveness of the assessment procedure. Studies using instruments designed to detect clinical levels of morbidity did not find this effect. Women with false-positive mammograms were less likely to return for the next round of screening [relative risk (RR) 0.97; 95% confidence interval (CI) 0.96 to 0.98] than those with normal mammograms, were more likely to have interval cancer [odds ratio (OR) 3.19 (95% CI 2.34 to 4.35)] and were more likely to have cancer detected at the next screening round [OR 2.15 (95% CI 1.55 to 2.98)]. - Limitations This study was limited to UK research and by the robustness of the included studies, which frequently failed to report quality indicators, for example failure to consider the risk of bias or confounding, or failure to report participants' demographic characteristics. - Conclusions We conclude that the experience of having a false-positive screening mammogram can cause breast cancer-specific psychological distress that may endure for up to 3 years, and reduce the likelihood that women will return for their next round of mammography screening. These results should be treated cautiously owing to inherent weakness of observational designs and weaknesses in reporting. Future research should include a qualitative interview study and observational studies that compare generic and disease-specific measures, collect demographic data and include women from different social and ethnic groups.

High-throughput prediction of eucalypt lignin syringyl/guaiacyl content using multivariate analysis: a comparison between mid-infrared, near-infrared, and Raman spectroscopies for model development

BACKGROUND: In order to rapidly and efficiently screen potential biofuel feedstock candidates for quintessential traits, robust high-throughput analytical techniques must be developed and honed. The traditional methods of measuring lignin syringyl/guaiacyl (S/G) ratio can be laborious, involve hazardous reagents, and/or be destructive. Vibrational spectroscopy can furnish high-throughput instrumentation without the limitations of the traditional techniques. Spectral data from mid-infrared, near-infrared, and Raman spectroscopies was combined with S/G ratios, obtained using pyrolysis molecular beam mass spectrometry, from 245 different eucalypt and Acacia trees across 17 species. Iterations of spectral processing allowed the assembly of robust predictive models using partial least squares (PLS). RESULTS: The PLS models were rigorously evaluated using three different randomly generated calibration and validation sets for each spectral processing approach. Root mean standard errors of prediction for validation sets were lowest for models comprised of Raman (0.13 to 0.16) and mid-infrared (0.13 to 0.15) spectral data, while near-infrared spectroscopy led to more erroneous predictions (0.18 to 0.21). Correlation coefficients (r) for the validation sets followed a similar pattern: Raman (0.89 to 0.91), mid-infrared (0.87 to 0.91), and near-infrared (0.79 to 0.82). These statistics signify that Raman and mid-infrared spectroscopy led to the most accurate predictions of S/G ratio in a diverse consortium of feedstocks. CONCLUSION: Eucalypts present an attractive option for biofuel and biochemical production. Given the assortment of over 900 different species of Eucalyptus and Corymbia, in addition to various species of Acacia, it is necessary to isolate those possessing ideal biofuel traits. This research has demonstrated the validity of vibrational spectroscopy to efficiently partition different potential biofuel feedstocks according to lignin S/G ratio, significantly reducing experiment and analysis time and expense while providing non-destructive, accurate, global, predictive models encompassing a diverse array of feedstocks.

Joseph A. Rosen Papers 1921-1938

With few exceptions, the bulk of the collection pertains to the work of the Agro-Joint. Records of the Agro-Joint Director General. Agreements of the American Relief Administration (ARA) and the Joint Distribution Committee with the Soviet government, 1922-1923. Agreements between the Agro-Joint and the Soviet government, 1924, 1927, 1928. Agreements of the Agro-Joint and the American Society for Jewish Farm Settlements (ASJFS) with the Soviet government, 1929, 1930, 1933, 1938. Materials relating to relief work of the JDC within the framework of the American Relief Administration, 1922, including the appointment of J. Rosen as the JDC representative at the ARA. Statistics, reports, miscellaneous correspondence relating to JDC activities in Russia. Minutes, memos, reports, legal documents, certificate of incorporation, and general correspondence relating to the ASJFS, its formation, fund-raising activities, 1927-1939. Records of the Agro-Joint Main Office, Moscow. Annual and periodi c reports of the Agro-Joint including statistics, financial estimates, financial reports, analyses of expenditures, relating to Agro-Joint work, 1924-1937. General correspondence files: incoming and outgoing letters, reports, and memoranda. Materials relating to land surveys and allocations in the Crimea: statistics, surveys, memos, correspondence, relating to the Salsk district, Chernomor district, Changar peninsula, Azov, Kuban, Odessa district, Samara district, Povolzhe, Krivoy Rog, Kherson, The Far East, Siberia. Materials relating to contacts with KOMZET. Correspondence, minutes of KOMZET meetings, statistical information, reports. By-laws of the OZET (Obshchestvo po Zemleustroystvu Trudyachtchikhsya Evreev - Association For the Settlement of Toiling Jews On Land) and AGRO-KUSTBANK (Evreysky Agrarno-Kustarny Bank - Jewish Agricultural and House Workers Bank). Register of Agro-Joint assets transferred to KOMZET. Records of the Agro-Joint Agricultural Department. Materials

Association of FOXE1 Polyalanine Repeat Region with Papillary Thyroid Cancer

CONTEXT: Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12-22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region. OBJECTIVE: The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters. DESIGN: This was a case-control study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS AND METHODS: The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 5667 samples from the Wellcome Trust Case Control Consortium). In vitro studies were performed to examine the protein expression, DNA binding, and transcriptional function for FOXE1 variants of different polyalanine tract lengths. RESULTS: All the genotyped SNP were in tight linkage disequilibrium, including the FOXE1 polyalanine repeat region. We confirmed the strong association of rs1867277 with PTC (overall P = 1 × 10(-7), odds ratio 1.84, confidence interval 1.31-2.57). rs1867277 was in tight linkage disequilibrium with the FOXE1 polyalanine repeat region (r(2) = 0.95). FOXE1(16Ala) was associated with PTC with an odds ratio of 2.23 (confidence interval 1.42-3.50; P = 0.0005). Functional studies in vitro showed that FOXE1(16Ala) was transcriptionally impaired compared with FOXE1(14Ala), which was not due to differences in protein expression or DNA binding. CONCLUSIONS: We have confirmed the previous association of FOXE1 with PTC. Our data suggest that the coding polyalanine expansion in FOXE1 may be responsible for the observed association between FOXE1 and PTC.

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10-8) level: 14q24.2 (rs227425, P-value 3.98 × 10-13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10-9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n 5 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis. © The Author 2013. Published by Oxford University Press.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Prediction of individual genetic risk to prostate cancer using a polygenic score

BACKGROUND Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction. Prostate 75:1467–1474, 2015. © 2015 Wiley Periodicals, Inc.