Combinations of SNP genotypes from the Wellcome Trust Case Control Study of bipolar patients.

OBJECTIVES: Combinations of genetic variants are the basis for polygenic disorders. We examined combinations of SNP genotypes taken from the 446 729 SNPs in The Wellcome Trust Case Control Study of bipolar patients. METHODS: Parallel computing by graphics processing units, cloud computing, and data mining tools were used to scan The Wellcome Trust data set for combinations. RESULTS: Two clusters of combinations were significantly associated with bipolar disorder. One cluster contained 68 combinations, each of which included five SNP genotypes. Of the 1998 patients, 305 had combinations from this cluster in their genome, but none of the 1500 controls had any of these combinations in their genome. The other cluster contained six combinations, each of which included five SNP genotypes. Of the 1998 patients, 515 had combinations from the cluster in their genome, but none of the 1500 controls had any of these combinations in their genome. CONCLUSION: Clusters of combinations of genetic variants can be considered general risk factors for polygenic disorders, whereas accumulation of combinations from the clusters in the genome of a patient can be considered a personal risk factor.

The Bermuda Triangle: The Pragmatics, Policies, and Principles for Data Sharing in the History of the Human Genome Project.

The Bermuda Principles for DNA sequence data sharing are an enduring legacy of the Human Genome Project (HGP). They were adopted by the HGP at a strategy meeting in Bermuda in February of 1996 and implemented in formal policies by early 1998, mandating daily release of HGP-funded DNA sequences into the public domain. The idea of daily sharing, we argue, emanated directly from strategies for large, goal-directed molecular biology projects first tested within the "community" of C. elegans researchers, and were introduced and defended for the HGP by the nematode biologists John Sulston and Robert Waterston. In the C. elegans community, and subsequently in the HGP, daily sharing served the pragmatic goals of quality control and project coordination. Yet in the HGP human genome, we also argue, the Bermuda Principles addressed concerns about gene patents impeding scientific advancement, and were aspirational and flexible in implementation and justification. They endured as an archetype for how rapid data sharing could be realized and rationalized, and permitted adaptation to the needs of various scientific communities. Yet in addition to the support of Sulston and Waterston, their adoption also depended on the clout of administrators at the US National Institutes of Health (NIH) and the UK nonprofit charity the Wellcome Trust, which together funded 90% of the HGP human sequencing effort. The other nations wishing to remain in the HGP consortium had to accommodate to the Bermuda Principles, requiring exceptions from incompatible existing or pending data access policies for publicly funded research in Germany, Japan, and France. We begin this story in 1963, with the biologist Sydney Brenner's proposal for a nematode research program at the Laboratory of Molecular Biology (LMB) at the University of Cambridge. We continue through 2003, with the completion of the HGP human reference genome, and conclude with observations about policy and the historiography of molecular biology.

The under-representation of minority ethnic groups in UK medical research.

Objectives . The paper investigates differences in engagement with medical research between White British and Black, Asian and Minority Ethnic (BAME) groups in the UK, using data from the Wellcome Trust Monitor (WTM). DESIGN: The study used two waves of the WTM (n = 2575) to examine associations between ethnic group and participation in medical research, and willingness to participate (WP) in medical research. Logistic regression models controlled for socio-economic and demographic factors, and relevant outlooks and experiences that are assumed to be markers of engagement. RESULTS: Respondents from the BAME group were less likely to have participated in medical research compared to those from the White British group, but there was only patchy evidence of small ethnic group differences in WP. Influences on engagement with medical research varied somewhat between the White British and BAME groups, in particular in relation to occupation, education, health, attitudes to medical science and belief. CONCLUSIONS: These findings consolidate previously context-specific evidence of BAME group under-representation in the UK, and highlight heterogeneity in that group. Efforts to address the under-representation of those from BAME groups might benefit from targeted strategies for recruitment and advocacy, although improved data sets are required to fully understand ethnic differences in engagement with medical research.

Where are all the surgeons in clinical academia?

INTRODUCTION: High-quality research into surgical disease will benefit surgical patients. Whereas nearly one-fifth of National Health Service (NHS) England consultants are surgeons, less than 5% of the government's health research funding supports surgical research. METHODS: Using an observational study, we identified surgeons in active research fellowships and on selection panels for the three largest pan-specialty medical funding bodies in the UK. We quantified the proportion of editorial board members that are surgeons, and the proportion of surgical research published over a 1-year period in the New England Journal of Medicine, The Lancet and the British Medical Journal. RESULTS: Some 185/1,579 (12%) of research fellowships held by clinicians were awarded to surgeons, with relatively fewer surgeons holding senior fellowships compared with predoctoral fellowships. Across the three research funding bodies, 9/165 (5%) of the clinical panel members were surgeons, whereas for the three pan-specialty journals, 5/84 (6%) of the clinical editorial board members were surgeons. Of the 541 original articles published by the same three journals, only 45 (8%) were classified as surgical. CONCLUSIONS: We show that surgeons were underrepresented across differing domains of clinical academia. The causes of this are likely multifactorial; there are fewer senior surgeons occupying decision-making positions, fewer role models in senior fellowship positions and surgical training may leave less time to engage in research. We propose further qualitative research within the surgical community, funding bodies and journals to understand the origins of the problem and begin to form evidence-based solutions.

Evaluating statistical significance in a meta-analysis by using numerical integration.

Meta-analysis is a method for enhancing statistical power through the integration of information from multiple studies. Various methods for integrating p-values (i.e., statistical significance), including Fisher's method under an independence assumption, the permutation method, and the decorrelation method, have been broadly used in bioinformatics and computational biotechnology studies. However, these methods have limitations related to statistical assumption, computing efficiency, and accuracy of statistical significance estimation. In this study, we proposed a numerical integration method and examined its theoretical properties. Simulation studies were conducted to evaluate its Type I error, statistical power, computational efficiency, and estimation accuracy, and the results were compared with those of other methods. The results demonstrate that our proposed method performs well in terms of Type I error, statistical power, computing efficiency (regardless of sample size), and statistical significance estimation accuracy. P-value data from multiple large-scale genome-wide association studies (GWASs) and transcriptome-wise association studies (TWASs) were analyzed. The results demonstrate that our proposed method can be used to identify critical genomic regions associated with rheumatoid arthritis and asthma, increase statistical significance in individual GWASs and TWASs, and control for false-positives more effectively than can Fisher's method under an independence assumption. We created the software package Pbine, available at GitHub (https://github.com/Yinchun-Lin/Pbine).

Converting Access Microbiology to an open research platform: community survey results.

Following the Microbiology Society's successful bid for a Learned Society Curation Award from the Wellcome Trust and Howard Hughes Medical Institute, the Society is converting our sound science, open access journal, Access Microbiology, to an open research platform. As part of this, we conducted a survey of our community to gauge current attitudes towards the platform and here we present some of these results. The majority of respondents (57 %) said they would always or sometimes want to remain anonymous on their peer review report, whilst 75 % of respondents said that as an author they would be happy to make the data underlying their research open. There was a clear desire for a range of research types that are often seen with sound science publications and rigorous research. An encouraging 94 % of respondents stated that the platform is somewhere they would consider publishing, demonstrating the enthusiasm in these respondents for a new publishing platform for their community. Given this data and that from our previous focus group research, the platform will launch as outlined in the original project proposal and adopt a transparent peer review model with an open data policy.

Converting Access Microbiology to an open research platform: focus group and AI review tool research results.

The Microbiology Society will be launching an open research platform in October 2021. Developed using funding from the Wellcome Trust and the Howard Hughes Medical Institute (HHMI), the platform will combine our current sound-science journal, Access Microbiology, with artificial intelligence (AI) review tools and many of the elements of a preprint server. In an effort to improve the rigour, reproducibility and transparency of the academic record, the Access Microbiology platform will host both preprints of articles and their Version of Record (VOR) publications, as well as the reviewer reports, Editor's decision, authors' response to reviewers and the AI review reports. To ensure the platform meets the needs of our community, in February 2020 we conducted focus group meetings with various stakeholders. Using articles previously submitted to Access Microbiology, we undertook testing of a range of potential AI review tools and investigated the technical feasibility and utility of including these tools as part of the platform. In keeping with the open and transparent ethos of the platform, we present here a summary of the focus group feedback and AI review tool testing.

Research in developing countries.

The rapid expansion over the last decade in medical research, sponsored by rich countries but undertaken in developing countries, has led to several reports and guidelines, three of which are excerpted here.

Genetic discrimination in life insurance: empirical evidence from a cross sectional survey of genetic support groups in the United Kingdom.

OBJECTIVES: To gather empirical evidence on any discrimination based on genetic information shown by the insurance industry in the United Kingdom and to assess how society is likely to handle future genetic information from tests for polygenic multifactorial conditions. DESIGN: Postal questionnaire survey. SUBJECTS: Sample (n=7000) of members from seven British support groups for families with genetic disorders and a representative sample (n=1033) of the general public who answered questions on applying for life insurance as part of an omnibus survey. MAIN OUTCOME MEASURES: Subjects were asked about their experiences with insurers, the medical profession, employers, and social services. Experiences with insurers are reported here. RESULTS: Altogether 33.4% of the study group had problems when applying for life insurance compared with 5% of applicants in the omnibus survey. Thirteen per cent of study respondents from subgroups who represented no adverse actuarial risk on genetic grounds reported that their treatment by insurers seemed to represent unjustified genetic discrimination. CONCLUSIONS: Life insurers may not be operating a consistent policy for assessing genetic information or acting in accord with the actuarial risks brought to them. The inconsistency suggests error rather than a corporate policy of discrimination based on genetic characteristics. Any future proposals for genetic testing for common or multifactorial disorders should be examined carefully.

H3Africa: a tipping point for a revolution in bioinformatics, genomics and health research in Africa.

BACKGROUND: A multi-million dollar research initiative involving the National Institutes of Health (NIH), Wellcome Trust and African scientists has been launched. The initiative, referred to as H3Africa, is an acronym that stands for Human Heredity and Health in Africa. Here, we outline what this initiative is set to achieve and the latest commitments of the key players as at October 2013. FINDINGS: The initiative has so far been awarded over $74 million in research grants. During the first set of awards announced in 2012, the NIH granted $5 million a year for a period of five years, while the Wellcome Trust doled out at least $12 million over the period to the research consortium. This was in addition to Wellcome Trust's provision of administrative support, scientific consultation and advanced training, all in collaboration with the African Society for Human Genetics. In addition, during the second set of awards announced in October 2013, the NIH awarded to the laudable initiative 10 new grants of up to $17 million over the next four years. CONCLUSIONS: H3Africa is poised to transform the face of research in genomics, bioinformatics and health in Africa. The capacity of African scientists will be enhanced through training and the better research facilities that will be acquired. Research collaborations between Africa and the West will grow and all stakeholders, including the funding partners, African scientists, scientists across the globe, physicians and patients will be the eventual winners.

Candidate disease gene prediction using Gentrepid: application to a genome-wide association study on coronary artery disease.

Current single-locus-based analyses and candidate disease gene prediction methodologies used in genome-wide association studies (GWAS) do not capitalize on the wealth of the underlying genetic data, nor functional data available from molecular biology. Here, we analyzed GWAS data from the Wellcome Trust Case Control Consortium (WTCCC) on coronary artery disease (CAD). Gentrepid uses a multiple-locus-based approach, drawing on protein pathway- or domain-based data to make predictions. Known disease genes may be used as additional information (seeded method) or predictions can be based entirely on GWAS single nucleotide polymorphisms (SNPs) (ab initio method). We looked in detail at specific predictions made by Gentrepid for CAD and compared these with known genetic data and the scientific literature. Gentrepid was able to extract known disease genes from the candidate search space and predict plausible novel disease genes from both known and novel WTCCC-implicated loci. The disease gene candidates are consistent with known biological information. The results demonstrate that this computational approach is feasible and a valuable discovery tool for geneticists.

Henry Solomon Wellcome: A philanthropist and a pioneer sponsor of medical research in the Sudan.

Henry Solomon Wellcome, the famous drug manufacturer had a fascinating association with the Sudan. Besides supporting tropical medicine research in this country, he established an extensive project in the Sudan that aimed at combining archeological excavations, philanthropy and social reform. This article is an archives-based account on this side of Wellcome's association with the Sudan. The article starts with Wellcome's early years in the American Midwest and the evolution of his career and his rise as a world-renowned drug manufacturer. After the battle of Omdurman, Wellcome visited Sudan in 1900 - 1901 where he offered to support the establishment of the research laboratories which later came to be known as the Wellcome Tropical Research Laboratories in Khartoum. He then became directly involved in the planning and running of extensive archeological excavations in the central Sudan. This project served as a field in which Wellcome found an outlet for his philanthropy. More than 4000 labourers were employed in Jebel Moya. Professional archeologists and anatomists were recruited by Wellcome to supervise the work, and all the requirements in terms of equipment were catered for. Wellcome devised a Savings Bank System whereby part of the earnings of each labourer were saved to him till the end of the season. He also introduced one of his innovations: aerial photography using box kite which was used for the first time in archeology. Wellcome made it a rule that no applicant should be turned away. The Camp Commandant had to find suitable work for each applicant, including the handicapped who were assigned to appropriate jobs like mending baskets or cutting grass for building huts. Wellcome's welfare work had a significant impact on the local inhabitants of Jebel Moya. Henry Solomon Wellcome, 1906. Oil painting by Hugh Goldwin Riviere. Credit: Wellcome Library.

Identification of susceptibility modules for coronary artery disease using a genome wide integrated network analysis.

Although recent genome-wide association studies (GWAS) have identified a handful of variants with best significance for coronary artery disease (CAD), it remains a challenge to summarize the underlying biological information from the abundant genotyping data. Here, we propose an integrated network analysis that effectively combines GWAS genotyping dataset, protein-protein interaction (PPI) database, literature and pathway annotation information. This three-step approach was illustrated for a comprehensive network analysis of CAD as the following. First, a network was constructed from PPI database and CAD seed genes mined from the available literatures. Then, susceptibility network modules were captured from the results of gene-based association tests. Finally, susceptibility modules were annotated with potential mechanisms for CAD via the KEGG pathway database. Our network analysis identified four susceptibility modules for CAD including a complex module that consisted of 15 functional inter-connected sub-modules, AGPAT3-AGPAT4-PPAP2B module, ITGA11-ITGB1 module and EMCN-SELL module. MAPK10 and COL4A2 among the top-scored focal adhesion pathway related module were the most significant genes (MAPK10: OR=32.5, P=3.5 × 10(-11); COL4A2: OR=2.7, P=2.8 × 10(-10)). The significance of the two genes were further validated by other two gene-based association tests (MAPK10: P=0.009 and 0.007; COL4A2: P=0.001 and 0.023) and another independent GWAS dataset (MAPK10: P=0.001; COL4A2: P=0.0004). Furthermore, 34 out of 44 previously reported CAD susceptibility genes were captured by our CAD PPI network and 17 of them were also significant genes. The susceptibility modules identified in our study might provide novel clues for the clarification of CAD pathogenesis in the future.