Democratic governance of genomics: the case of UK Biobank

Biobanks are collections of human biological tissue used for genomics research. This promises a better understanding of the gene-based contribution to common disease and development of a more personalized approach to healthcare with safer drugs and more effective treatment. However, biobanks are also controversial owing to the ethical, legal, social and political issues raised about their collection and use of biological samples. Therefore, their democratic governance is not only a normative challenge but also an empirical one. This paper is concerned with both challenges: it attempts to “evaluate” processes of democratic governance of genomics by focusing on the case of UK Biobank. The overall argument is that although the UK Biobank performs well in terms of general democratic governance structures, there are epistemological and practical limits to specific democratic governance processes.     

Cognitive Test Scores in UK Biobank: Data Reduction in 480,416 Participants and Longitudinal Stability in 20,346 Participants

UK Biobank includes 502,649 middle- and older-aged adults from the general population who have undergone detailed phenotypic assessment. The majority of participants completed tests of cognitive functioning, and on average four years later a sub-group of N = 20,346 participants repeated most of the assessment. These measures will be used in a range of future studies of health outcomes in this cohort. The format and content of the cognitive tasks were partly novel. The aim of the present study was to validate and characterize the cognitive data: to describe the inter-correlational structure of the cognitive variables at baseline assessment, and the degree of stability in scores across longitudinal assessment. Baseline cognitive data were used to examine the inter-correlational/factor-structure, using principal components analysis (PCA). We also assessed the degree of stability in cognitive scores in the subsample of participants with repeat data. The different tests of cognitive ability showed significant raw inter-correlations in the expected directions. PCA suggested a one-factor solution (eigenvalue = 1.60), which accounted for around 40% of the variance. Scores showed varying levels of stability across time-points (intraclass correlation range = 0.16 to 0.65). UK Biobank cognitive data has the potential to be a significant resource for researchers looking to investigate predictors and modifiers of cognitive abilities and associated health outcomes in the general population.     

Human genetic banking: altruism,benefit and consent

This article considers how we should frame the ethical issues raised by current proposals for large‐scale genebanks with on‐going links to medical and lifestyle data, such as the Wellcome Trust and Medical Research Council's ‘UK Biobank’. As recent scandals such as Alder Hey have emphasised, there are complex issues concerning the informed consent of donors that need to be carefully considered. However, we believe that a preoccupation with informed consent obscures important questions about the purposes to which such collections are put, not least that they may be only haphazardly used for research (especially that of commercial interest)—an end that would not fairly reflect the original altruistic motivation of donors, and the trust they must invest. We therefore argue that custodians of such databases take on a weighty pro‐active duty, to encourage public debate about the ends of such collections and to sponsor research that reflects publicly agreed priorities and provides public benefits.     

Reflexive governance in biobanking: on the value of policy led approaches and the need to recognise the limits of law

Although a few jurisdictions around the world have legislated in response to the phenomenon of biobanking, the far more common response has been policy led with funders and other stakeholders initiating multi-level policy initiatives to guide biobanking practice. An example of this is UK Biobank which has developed and operates according to an Ethics and Governance Framework. Such an instrument has no basis in law and yet it has played a crucial role in the set up and ongoing management of the resource. It will continue to do so, as related policies emerge, such as access and intellectual property policies. Numerous biobanking initiatives have similar high-level policy documents that guide decisions and practice. These are often framed as a commitment to participants, researchers and society more broadly and invoke notions such as the public good and the public interest. As such, they serve as a benchmark against which to measure a biobank’s performance. Moreover, policies become an important means by which biobankers are held accountable. This article critically analyses this policy-driven phenomenon asking how effectively policy—often as an alternative to law—serves to police and to promote biobanking. It argues that a policy of reflexive governance—defined and developed herein—can best meet the challenges faced by many biobanks and without the need for recourse to law.     

Suitability of UK Biobank Retinal Images for Automatic Analysis of Morphometric Properties of the Vasculature

PurposeTo assess the suitability of retinal images held in the UK Biobank - the largest retinal data repository in a prospective population-based cohort - for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease.MethodsNon-mydriatic fundus images from both eyes of 2,690 participants - people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345) - were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry.ResultsTotal operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (p<0.0001). Cases exhibited more acute arteriolar branching angles (p=0.02) as well as lower arteriolar and venular tortuosity (p<0.0001).ConclusionsA proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group.     

Exploiting collider bias to apply two-sample summary data Mendelian randomization methods to one-sample individual level data

Over the last decade the availability of SNP-trait associations from genome-wide association studies has led to an array of methods for performing Mendelian randomization studies using only summary statistics. A common feature of these methods, besides their intuitive simplicity, is the ability to combine data from several sources, incorporate multiple variants and account for biases due to weak instruments and pleiotropy. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well developed summary data methods to individual level data, and to explore the use of more sophisticated causal methods allowing for non-linearity and effect modification.In this paper we describe a general procedure for optimally applying any two sample summary data method using one sample data. Our procedure first performs a meta-analysis of summary data estimates that are intentionally contaminated by collider bias between the genetic instruments and unmeasured confounders, due to conditioning on the observed exposure. These estimates are then used to correct the standard observational association between an exposure and outcome. Simulations are conducted to demonstrate the method’s performance against naive applications of two sample summary data MR. We apply the approach to the UK Biobank cohort to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes.Our approach can be viewed as a generalization of Dudbridge et al. (Nat. Comm. 10: 1561), who developed a technique to adjust for index event bias when uncovering genetic predictors of disease progression based on case-only data. Our work serves to clarify that in any one sample MR analysis, it can be advantageous to estimate causal relationships by artificially inducing and then correcting for collider bias.     

Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study

BackgroundAtrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR).Methods and findingsWeighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87–0.96, P = 2 × 10⁻⁴ and OR 0.94; 95% CI: 0.93–0.96, P = 2 × 10⁻¹⁹, respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.ConclusionsIn UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.

In a Mendelian randomization analysis, Parag Gajendragadkar and colleagues investigate associations between genetically-predicted EEG parameters and risk of atrial fibrillation among UK Biobank participants.     

2020年后生物多样性保护需要建立新的资金机制

《生物多样性公约》第十五次缔约方大会(COP15)将评估全球生物多样性保护已有进展, 审议并通过“2020年后全球生物多样性框架”, 后者是实现2050愿景“与自然和谐相处”的关键, 有助于达成联合国可持续发展的目标。生物多样性资金机制现在是将来也是实施全球生物多样性保护行动计划的重要保证。根据《生物多样性公约》信息交换所的数据, 目前各缔约方每年对本国生物多样性保护的投资额度占其当年国内生产总值(GDP)的比例比较小。中国作为发展中国家, 2015年时生物多样性保护资金投入占GDP比例为0.255%, 在世界各国中处于比较高的水平。近年中国对生物多样性保护的投入连年增加, 2019年时已经达约0.6%。有研究表明, 目前全球每年生物多样性保护资金的缺口至少500亿美元, 未来十年还有更大的资金缺口, 而且当前已有生物多样性资金渠道比较单一, 并存在一些短板, 远远不能满足生物多样性保护行动的要求, 急需建立新的资金机制, 调动更多资源, 推动2030年生物多样性保护任务和目标的实现。《生物多样性公约》的资金机制可以与包括《联合国气候变化框架公约》在内的其他相关环境公约协同增效, 比如基于自然的解决方案将生物多样性保护与气候变化减缓等环境目标联系起来。中国作为COP15的东道国, 有积极协调磋商的责任, 力求在大会上推动形成一个新的资金机制, 即全球生物多样性保护基金, 为“2020年后全球生物多样性框架”的实施保驾护航。新的生物多样性保护资金机制将独立于现有的生物多样性保护资金机制, 具有多样化投资渠道并引入绩效评估机制, 将经费与任务目标关联, 提高资金的使用效率, 支持发展中国家的生物多样性保护行动。     

Leveraging eQTLs to identify individual-level tissue of interest for a complex trait

Genetic predisposition for complex traits often acts through multiple tissues at different time points during development. As a simple example, the genetic predisposition for obesity could be manifested either through inherited variants that control metabolism through regulation of genes expressed in the brain, or that control fat storage through dysregulation of genes expressed in adipose tissue, or both. Here we describe a statistical approach that leverages tissue-specific expression quantitative trait loci (eQTLs) corresponding to tissue-specific genes to prioritize a relevant tissue underlying the genetic predisposition of a given individual for a complex trait. Unlike existing approaches that prioritize relevant tissues for the trait in the population, our approach probabilistically quantifies the tissue-wise genetic contribution to the trait for a given individual. We hypothesize that for a subgroup of individuals the genetic contribution to the trait can be mediated primarily through a specific tissue. Through simulations using the UK Biobank, we show that our approach can predict the relevant tissue accurately and can cluster individuals according to their tissue-specific genetic architecture. We analyze body mass index (BMI) and waist to hip ratio adjusted for BMI (WHRadjBMI) in the UK Biobank to identify subgroups of individuals whose genetic predisposition act primarily through brain versus adipose tissue, and adipose versus muscle tissue, respectively. Notably, we find that these individuals have specific phenotypic features beyond BMI and WHRadjBMI that distinguish them from random individuals in the data, suggesting biological effects of tissue-specific genetic contribution for these traits.     

Genetic research on the UK population--do new principles need to be developed?

Governments around the world are beginning to generate population databases as resources for genetic research. In the UK, a proposal has been tabled that plans to incorporate National Health Service information--a move that will effectively create a database of around 60 million. However, this new population collection will not conform to standards established by other national genetic databases, and the UK government report has not accounted for key ethical issues.     

A Proposed Approach to Informed Consent for Biobanks in China

Biobanks are potential goldmines for genomics research. They have become increasingly common as a means to determine the relationship between lifestyle, environmental exposures and predisposition to genetic disease. More and more countries are developing massive national scale biobanks, including Iceland, the UK and Estonia. Now several large‐scale regional and national biobanks are planned in China, such as Shanghai Biobank, which is defined as a key‐element in Shanghai's twelfth five‐year Development Plan of Science and Technology. It is imperative that the authors who are in charge of the ethical aspect of Shanghai Biobank discuss the ethical aspects of these biobanks up front. Currently there is a great deal of heterogeneity in the approaches to informed consent taken by different countries. In the article, after briefly introducing the biobanks in China, we focus on the three most common approaches: classical informed consent, tiered consent, and one‐time general (or blanket) consent, and propose a version of the latter for China, based on compelling arguments.     

Treating anemia of chronic kidney disease in the primary care setting: cardiovascular outcomes and management recommendations

Background

Recent policy and organisational changes within UK primary care have emphasised graduated access to care, speed of access to the first available general practitioner (GP) and care being provided by a range of healthcare professionals. These trends have been strengthened by the current GP contract and Quality and Outcomes Framework (QOF). Concern has been expressed that the potential for personal care is being diminished as a result and that this will reduce quality standards. This paper presents data from a study that explored with patients and GPs what personal care means and whether it has continuing importance to them.

Methods

A semi-structured questionnaire was used to interview participants and Framework Analysis supported analysis of emerging themes. Twenty-nine patients, mainly women with young children, and twenty-three GPs were interviewed from seven practices in Lothian, Scotland, ranged by practice size and relative deprivation score.

Results and Discussion

Personal care was defined mainly, though not exclusively, as care given within the context of a continuing relationship in which there is an interpersonal connection and the doctor adopts a particular consultation style. Defined in this way, it was reported to have benefits for both health outcomes and patients' experience of care. In particular, such care was thought to be beneficial in attending to the emotions that can be elicited when seeking and receiving health care and in enabling patients to be known by doctors as legitimate seekers of care from the health service. Its importance was described as being dependent upon the nature of the health problem and patients' wider familial and social circumstances. In particular, it was found to provide support to patients in their parenting and other familial caring roles.

Conclusion

Personal care has continuing salience to patients and GPs in modern primary care in the UK. Patients equate the experience of care, not just outcomes, with high quality care. As it is mainly conceptualised and experienced as care within the context of a continuing relationship, policies and organisational arrangements that support and give incentives to this must be in place. These preferences are not strongly reflected in the QOF. Specific questions need to be addressed by future audit and research on the impact of the contract on these aspects of service.     

英国初级卫生保健质量与结果框架解析

目的 了解英国初级卫生保健质量与结果框架,为改善我国全科服务质量提供经验借鉴。 方法 文献综述与定性访谈。 结果 质量与结果框架作为全科服务合同的一部分,目的是通过引进激励机制改进服务质量,制定一套反映全科医疗服务质量的指标和评分体系,通过综合打分对全科医生的服务进行衡量。结论 在完善的组织管理、疾病登记体系和信息系统的支撑下,质量与结果框架有利于对全科服务进行标准化,统一的定价和支付体系有利于降低不同地区初级卫生保健的服务差异,激励了全科诊所服务的积极性。但也有专家学者指出了其中的一些弊端,有待进一步修正和完善。     

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10^-05), with good concordance between GAME-ON and UK Biobank (I² = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.     

Frequency and Distribution of Refractive Error in Adult Life: Methodology and Findings of the UK Biobank Study

PurposeTo report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, in the UK.MethodsU K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40–69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio-demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview.ResultsFifty four percent of participants aged 40–69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40–44 years increasing to 46% at 65–69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White).ConclusionsRefractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study.     

Between the individual and the community: the impact of genetics on ethical models

This paper discusses how genetics is influencing ethical frameworks with particular focus on the effectiveness and appropriateness of individual and communal models. It suggests that genetics supports a relational understanding of the person and therefore that genetic ethics requires ethical models which respect both individuals and groups. First, the inadequacy of individualistic frameworks – at conceptual, ethical and practical levels – is outlined. Second, the “communal turn” in genetic ethics in both clinical and population ethics is considered. Third, it is claimed that this communal turn is applicable to genetic ethics in general and to illustrate this two further examples are explored: those of UK Biobank and personalized medicine. The paper concludes that ethical frameworks in genetic ethics must accommodate both group and individual concerns.     

A new United States Pharmacopeia (USP) Chapter 1046: cell and gene therapy products

The United States Pharmacopeia (USP) has published the first draft of a new information chapter on cell and gene therapy products in January, 2000. The chapter discusses the manufacturing and testing cell and gene therapy products. It is intended for people working in the field as well as for pharmacists and clinicians who would like more information on this subject. This article outlines the background of USP and explains how it became involved with cell and gene therapy and what an information chapter is. It details the subjects covered by the chapter and the philosophy behind the chapter. This draft will be revised based on comments received from the public and then published as a revision subject to further comments before it becomes an official chapter in a supplement to USP 24-NF 19.     

TACKLING SOCIALLY DETERMINED DENTAL INEQUALITIES: ETHICAL ASPECTS OF CHILDSMILE, THE NATIONAL CHILD ORAL HEALTH DEMONSTRATION PROGRAMME IN SCOTLAND

Many ethical issues are posed by public health interventions. Although abstract theorizing about these issues can be useful, it is the application of ethical theory to real cases which will ultimately be of benefit in decision-making. To this end, this paper will analyse the ethical issues involved in Childsmile, a national oral health demonstration programme in Scotland that aims to improve the oral health of the nation's children and reduce dental inequalities through a combination of targeted and universal interventions. With Scotland's level of dental caries among the worst in Europe, Childsmile represents one of the largest programmes of work aimed at combating oral health inequalities in the UK. The areas of ethical interest include several contrasting themes: reducing health inequalities and improving health; universal and targeted interventions; political values and evidence base; prevention and treatment; and underlying all of these, justice and utility.     

A review of bioinformatics education in the UK

If the completion of the first draft of the human genome represents the coming of age of bioinformatics, then the emergence of bioinformatics as a university degree subject represents its establishment. In this paper bioinformatics as a subject for formal study is discussed, rather than as a subject for research, and a selection of the taught, mainly graduate, courses currently available in the UK are reviewed. Throughout, the author tries to draw parallels between the integration of bioinformatics into biomedical research and teaching today, and that of molecular biology, two decades ago. Others have made this analogy between these two relatively young disciplines. Although research sources are referenced, the author makes no pretence of objectivity. This article contains his opinions, and those of a number of current bioinformatics course organisers whose comments on the subject were solicited in advance specifically for this paper. The course organisers kindly advised how they planned their curricula, and described the special strengths of their programmes. Comments from present and former students of several bioinformatics degree programmes were also solicited. Except where individuals are directly quoted, any opinions expressed herein should be considered the author's. Compared with its sister piece [Marion Zatz, in previous issue of Briefings in Bioinformatics pp. 353], this paper is less about funding policy--which, in the UK, has lately (if belatedly) been more generous towards bioinformatics teaching--than it is about practice and content; the requirements of the bioinformatics research communities, the corresponding emphases of bioinformatics courses, and the general market for holders of bioinformatics degrees. Individual courses are cited throughout as examples, but the final section contains a full annotated listing with URL addresses. Based on the author's own experience of practising and teaching bioinformatics, he describes the skills he believes will be most useful to bioinformaticians in the near future and suggests ways to prepare students of bioinformatics for a fall in demand for those abilities.     

Uncertainty in ecological status assessments of lakes and rivers using diatoms

The EU’s Water Framework Directive requires all surface water bodies to be classified according to their ecological status. As biological communities show both spatial and temporal heterogeneity, expressions of ecological status will, inevitably, have an element of uncertainty associated with them. A consequence of this environmental heterogeneity is that there is a risk that status inferred from one or more samples is different to the true status of that water body. In order to quantify the scale of temporal uncertainty associated with benthic diatoms, replicate samples were collected from sites across the ecological status gradient in lakes and rivers in the UK. Variability (expressed as standard deviation of temporal replicate samples from a single site) could be described using a polynomial function and this was then used to calculate the risk of placing a water body in the wrong ecological status class. This risk varied depending on the distance from the class boundaries and the number of replicates. Based on these data, we recommend that ecological status is determined from a number of samples collected from a site over a period of time.