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  • ItemPublished versionOpen Access
    Participants’ perspectives and preferences on clinical trial result dissemination: The TRUST Thyroid Trial experience
    (F1000 Research, 2018-04-12) Sinnott, C; Racine, Emmy; Hurley, Caroline; Cheung, Aoife; Kearney, Patricia; Smithson, Henry; Sinnott, Carol [0000-0002-8620-7461]
    Background: While there is an increasing consensus that clinical trial results should be shared with trial participants, there is a lack of evidence on the most appropriate methods. The aim of this study is to use a patient and public involvement (PPI) approach to identify, develop and evaluate a patient-preferred method of receiving results of the Thyroid Hormone Replacement for Subclinical Hypo-Thyroidism Trial (TRUST). Methods: This is a mixed methods study with three consecutive phases. Phase 1 iteratively developed a patient-preferred result method using semi-structured focus groups and a consensus-orientated-decision model, a PPI group to refine the method and adult literacy review for plain English assessment. Phase 2 was a single-blind parallel group trial. Irish TRUST participants were randomised to the intervention (patient-preferred method) and control group (standard method developed by lead study site). Phase 3 used a patient understanding questionnaire to compare patient understanding of results between the two methods. Results: Patients want to receive results of clinical trials, with qualitative findings indicating three key themes including ‘acknowledgement of individual contribution’, ‘contributing for a collective benefit’ and ‘receiving accessible and easy to understand results’. Building on these findings, a patient-preferred method of receiving results was developed as described above. TRUST participants (n=101) were randomised to the intervention. The questionnaire response rate was 74% for the intervention group and 62% for the control group. There were no differences in patient understanding between the two methods. Conclusions: We have demonstrated that it is feasible to conduct PPI with regard to the dissemination of results. The study identified and developed a patient-preferred method of receiving clinical trial results for older adults over 65 years. Although, in this study PPI did not influence patients’ final understanding of results, it provides a record of the process of conducting PPI within the clinical trial setting.
  • ItemPublished versionOpen Access
    Community-based pre-pregnancy care programme improves pregnancy preparation in women with pregestational diabetes.
    (Springer, 2018-05-09) Yamamoto, Jennifer M; Hughes, Deborah JF; Evans, Mark L; Karunakaran, Vithian; Clark, John DA; Morrish, Nicholas J; Rayman, Gerry A; Winocour, Peter H; Hambling, Clare; Harries, Amanda W; Sampson, Michael J; Murphy, Helen R; Evans, Mark [0000-0001-8122-8987]; Hambling, Clare [0000-0001-5851-6307]
    AIMS/HYPOTHESIS: Women with diabetes remain at increased risk of adverse pregnancy outcomes associated with poor pregnancy preparation. However, women with type 2 diabetes are less aware of and less likely to access pre-pregnancy care (PPC) compared with women with type 1 diabetes. We developed and evaluated a community-based PPC programme with the aim of improving pregnancy preparation in all women with pregestational diabetes. METHODS: This was a prospective cohort study comparing pregnancy preparation measures before and during/after the PPC intervention in women with pre-existing diabetes from 1 June 2013 to 28 February 2017. The setting was 422 primary care practices and ten National Health Service specialist antenatal diabetes clinics. A multifaceted approach was taken to engage women with diabetes and community healthcare teams. This included identifying and sending PPC information leaflets to all eligible women, electronic preconception care templates, online education modules and resources, and regional meetings and educational events. Key outcomes were preconception folic acid supplementation, maternal HbA1c level, use of potentially harmful medications at conception and gestational age at first presentation, before and during/after the PPC programme. RESULTS: A total of 306 (73%) primary care practices actively participated in the PPC programme. Primary care databases were used to identify 5075 women with diabetes aged 18-45 years. PPC leaflets were provided to 4558 (89.8%) eligible women. There were 842 consecutive pregnancies in women with diabetes: 502 before and 340 during/after the PPC intervention. During/after the PPC intervention, pregnant women with type 2 diabetes were more likely to achieve target HbA1c levels ≤48 mmol/mol (6.5%) (44.4% of women before vs 58.5% of women during/after PPC intervention; p = 0.016) and to take 5 mg folic acid daily (23.5% and 41.8%; p = 0.001). There was an almost threefold improvement in 'optimal' pregnancy preparation in women with type 2 diabetes (5.8% and 15.1%; p = 0.021). Women with type 1 diabetes presented for earlier antenatal care during/after PPC (54.0% vs 67.3% before 8 weeks' gestation; p = 0.003) with no other changes. CONCLUSIONS/INTERPRETATION: A pragmatic community-based PPC programme was associated with clinically relevant improvements in pregnancy preparation in women with type 2 diabetes. To our knowledge, this is the first community-based PPC intervention to improve pregnancy preparation for women with type 2 diabetes. DATA AVAILABILITY: Further details of the data collection methodology, individual clinic data and the full audit reports for healthcare professionals and service users are available from .
  • ItemPublished versionOpen Access
    The MR-Base platform supports systematic causal inference across the human phenome.
    (eLife Sciences Publications, 2018-05-30) Hemani, Gibran; Zheng, Jie; Elsworth, Benjamin; Wade, Kaitlin H; Haberland, Valeriia; Baird, Denis; Laurin, Charles; Burgess, Stephen; Bowden, Jack; Langdon, Ryan; Tan, Vanessa Y; Yarmolinsky, James; Shihab, Hashem A; Timpson, Nicholas J; Evans, David M; Relton, Caroline; Martin, Richard M; Davey Smith, George; Gaunt, Tom R; Haycock, Philip C; Burgess, Stephen [0000-0001-5365-8760]
    Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base ( a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.
  • ItemPublished versionOpen Access
    Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data.
    (Annual Reviews, Inc., 2018-08) Burgess, Stephen; Foley, Christopher N; Zuber, Verena; Burgess, Stephen [0000-0001-5365-8760]; Foley, Christopher [0000-0002-0970-2610]; Zuber, Verena [0000-0001-9827-1877]
    An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious. We review the Mendelian randomization paradigm for making causal inferences using genetic variants. We consider monogenic analysis, in which genetic variants are taken from a single gene region, and polygenic analysis, which includes variants from multiple regions. We focus on answering two questions: When can Mendelian randomization be used to make reliable causal inferences, and when can it be used to make relevant causal inferences? Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see for revised estimates.
  • ItemAccepted versionOpen Access
    Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial.
    (IOS Press, 2018-02-20) Barbera, Mariagnese; Mangialasche, Francesca; Jongstra, Susan; Guillemont, Juliette; Ngandu, Tiia; Beishuizen, Cathrien; Coley, Nicola; Brayne, Carol; Andrieu, Sandrine; Richard, Edo; Soininen, Hilkka; Kivipelto, Miia; HATICE study group; Brayne, Carol [0000-0001-5307-663X]
    BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.
  • ItemPublished versionOpen Access
    Attachment histories and futures: reply to Vicedo’s ‘Putting attachment in its place’
    (Taylor & Francis, 2020) Duschinsky, RN; van IJzendoorn, Marinus; Foster, Sarah; Reijman, Sophie; Lionetti, Francesca; Duschinsky, Robbie [0000-0003-2023-5328]
    For Vicedo, ‘putting attachment in its place’ seems to entail two aspects. The first is working to understand the rise of attachment theory and its place within the history of knowledge practices. The second is to criticize the validity of attachment theory. In this reply, we appraise three criti- cisms made by Vicedo of attachment theory, chosen as points for 15 sustaining a dialogue. Our main point in this reply is that, in excluding the work of attachment researchers after Ainsworth from consideration, Vicedo’s work is not yet able to properly ‘put attachment in its place’, in either sense of the phrase. At most, she puts Bowlby in the 1950s–1960s in his place, but without speaking effectively to subsequent attachment 20 research. In our view, not just the validity, but the very meaning of attachment as a scientific research programme cannot be understood outside of its temporal context, and the relationship this entails between theory and research, past and future.
  • ItemPublished versionOpen Access
    What are the implications for practice that arise from studies of medication taking? A systematic review of qualitative research.
    (Public Library of Science (PLoS), 2018) Rashid, Mohammed Ahmed; Llanwarne, Nadia; Heyns, Natalie; Walter, Fiona; Mant, Jonathan; Walter, Fiona [0000-0002-7191-6476]; Mant, Jonathan [0000-0002-9531-0268]
    BACKGROUND: Despite several decades of evidence supporting the benefits of taking medications in various diseases and healthcare settings, a significant proportion of prescribed treatments are not taken. This review sought to synthesise qualitative research exploring experiences of medication taking around the world, and to determine whether there were consistent messages arising from these studies. METHODS AND FINDINGS: 5 databases (MEDLINE, PsycINFO, EMBASE, SCOPUS, CINAHL) were systematically searched to identify published research papers using qualitative methodologies, which explored medication-taking experiences in patients, citizens, carers, relatives and clinicians. Data were extracted independently by at least two clinician reviewers. Implications for practice from individual papers were charted and coded using thematic content analysis. These were then cross-tabulated with research paper categories to explore emergent patterns with particular implications for practice. 192 papers from 34 different countries were included in the review. Implications for practice fitted into 11 categories: increase family involvement, increase clinician involvement, promote personalised management, address practical barriers, provide ongoing support, promote self-management, adopt a patient-centred approach, improve patient education, address system barriers, increase access to non-prescribing clinicians and improve clinician training. These implications for practice were generally evenly spread across research paper categories. CONCLUSIONS: Implications for practice from the published qualitative literature exploring medication-taking are notably consistent across research methods, disease categories and geographical settings. More recent clinical trials of interventions to improve adherence have started to draw on these findings by focussing on improving clinical interactions and involving patients in healthcare decisions. Promoting patient education and self-management have been widely advocated, and improvements at a system level have been frequently cited in studies from developing countries and those relating to communicable diseases. Regardless of the setting, clinicians and policymakers around the world can focus efforts to improve medication-taking by considering a number of consistently emerging findings.
  • ItemAccepted versionOpen Access
    Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis.
    (American Diabetes Association, 2018-06) Kröger, Janine; Meidtner, Karina; Stefan, Norbert; Guevara, Marcela; Kerrison, Nicola D; Ardanaz, Eva; Aune, Dagfinn; Boeing, Heiner; Dorronsoro, Miren; Dow, Courtney; Fagherazzi, Guy; Franks, Paul W; Freisling, Heinz; Gunter, Marc J; Huerta, José María; Kaaks, Rudolf; Key, Timothy J; Khaw, Kay Tee; Krogh, Vittorio; Kühn, Tilman; Mancini, Francesca Romana; Mattiello, Amalia; Nilsson, Peter M; Olsen, Anja; Overvad, Kim; Palli, Domenico; Quirós, J Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sala, Núria; Salamanca-Fernández, Elena; Sluijs, Ivonne; Spijkerman, Annemieke MW; Tjonneland, Anne; Tsilidis, Konstantinos K; Tumino, Rosario; van der Schouw, Yvonne T; Forouhi, Nita G; Sharp, Stephen J; Langenberg, Claudia; Riboli, Elio; Schulze, Matthias B; Wareham, Nicholas J; Kröger, Janine [0000-0002-7496-3665]; Stefan, Norbert [0000-0002-2186-9595]; Fagherazzi, Guy [0000-0001-5033-5966]; Franks, Paul W [0000-0002-0520-7604]; Forouhi, Nita G [0000-0002-5041-248X]; Schulze, Matthias B [0000-0002-0830-5277]
    Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 µg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.
  • ItemAccepted versionOpen Access
    Handbook of Applied Modelling: Non-Gaussian and Correlated Data; Jamie D. Riggs and Trent L. Lalonde; 2017; Cambridge University, University Printing House, Shaftesbury Road, Cambridge CB2 8BS; 236 pp; Hardback £79.99, Paperback £25.99 eBook £23.99; ISBN-13: 978-1316601051.
    (Wiley-Blackwell) Pilling, Mark; Pilling, Mark [0000-0002-7446-6597]
    This first edition seeks to aid applied practitioners or analysts to explore wider classes of models for their data. It explains the processes of data examination, model selection and diagnostics in an accessible style, but which includes dense sections with lots of reliable advice with some brief technical explanations. The methods are illustrated on a small number of largish datasets, demonstrating progressive improvements chapter-by-chapter by repeatedly modelling the same datasets (although without typical textbook chapter-end example problems). The output and B&W graphics are based on R whose code is provided (with some minor typos). As of writing, the parallel SAS code was yet to be made available. This is neither a study textbook nor a technical manual, but rather a distillation of model-building vignettes with an American and astronomy slant in places. Even as an experienced analyst, I found the elucidated analysis considerations and the range of diagnostic approaches and interpretations extremely useful, while learning of a number of more current diagnostic statistics and plots (e.g. logistic histogram, QICu for GEE). While avoiding too much theory, this slim 236 page book packs in a lot of information on fitting a wide range of models. However this consequently means that some terms are used but not explained (e.g. loess, Wald); the index could be more detailed; certain model types are ignored (e.g. Bayesian, GAM); and the analysis examples are not comprehensive but instead suddenly lead to the “most appropriate” model (e.g. a ZIPIG in Chapter 9). One key weakness is not showing all the model-building process: this is referenced rather than explicitly shown. The authors also seem to avoid defining their threshold for significance. Their choice of specialised examples also means they focus on the problems of large datasets (i.e. overly conservative tests) rather than problems of small datasets (i.e. over-fitting). Arguably they imply simpler models are not useful, but most of the modelling issues addressed in these example datasets are clearly and expertly examined. This book is excellent for i) helping match model types to data, ii) showing the most typically useful model classes, iii) explaining which diagnostics are relevant, and iv) linking to references. It easily succeeds in its ambition as an introductory book for such models, encouraging users to adopt more advanced approaches through a few, key, worked examples, whilst tantalisingly acting as a gateway to more comprehensive references.
  • ItemPublished versionOpen Access
    (Ovid Technologies (Wolters Kluwer Health), 2018) McManus, R; Mant, J; Franssen, M; Nickless, A; Schwartz, C; Hodgkinson, J; Bradburn, P; Farmer, A; Grant, S; Greenfield, S; Heneghan, C; Jowett, S; Martin, U; Milner, S; Monahan, M; Mort, S; Ogburn, E; Perera-Salazar, R; Shah, S; Yu, L; Tarrasenko, L; Hobbs, R; Mant, Jonathan [0000-0002-9531-0268]
    Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared to usual care.
  • ItemPublished versionOpen Access
    Nutritional labelling for healthier food or non-alcoholic drink purchasing and consumption.
    (Wiley, 2018-02-27) Crockett, Rachel A; King, Sarah E; Marteau, Theresa M; Prevost, AT; Bignardi, Giacomo; Roberts, Nia W; Stubbs, Brendon; Hollands, Gareth J; Jebb, Susan A; Marteau, Theresa [0000-0003-3025-1129]; Hollands, Gareth [0000-0002-0492-3924]
    BACKGROUND: Nutritional labelling is advocated as a means to promote healthier food purchasing and consumption, including lower energy intake. Internationally, many different nutritional labelling schemes have been introduced. There is no consensus on whether such labelling is effective in promoting healthier behaviour. OBJECTIVES: To assess the impact of nutritional labelling for food and non-alcoholic drinks on purchasing and consumption of healthier items. Our secondary objective was to explore possible effect moderators of nutritional labelling on purchasing and consumption. SEARCH METHODS: We searched 13 electronic databases including CENTRAL, MEDLINE and Embase to 26 April 2017. We also handsearched references and citations and sought unpublished studies through websites and trials registries. SELECTION CRITERIA: Eligible studies: were randomised or quasi-randomised controlled trials (RCTs/Q-RCTs), controlled before-and-after studies, or interrupted time series (ITS) studies; compared a labelled product (with information on nutrients or energy) with the same product without a nutritional label; assessed objectively measured purchasing or consumption of foods or non-alcoholic drinks in real-world or laboratory settings. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of bias' tool and GRADE to assess the quality of evidence. We pooled studies that evaluated similar interventions and outcomes using a random-effects meta-analysis, and we synthesised data from other studies in a narrative summary. MAIN RESULTS: We included 28 studies, comprising 17 RCTs, 5 Q-RCTs and 6 ITS studies. Most (21/28) took place in the USA, and 19 took place in university settings, 14 of which mainly involved university students or staff. Most (20/28) studies assessed the impact of labelling on menus or menu boards, or nutritional labelling placed on, or adjacent to, a range of foods or drinks from which participants could choose. Eight studies provided participants with only one labelled food or drink option (in which labelling was present on a container or packaging, adjacent to the food or on a display board) and measured the amount consumed. The most frequently assessed labelling type was energy (i.e. calorie) information (12/28).Eleven studies assessed the impact of nutritional labelling on purchasing food or drink options in real-world settings, including purchases from vending machines (one cluster-RCT), grocery stores (one ITS), or restaurants, cafeterias or coffee shops (three RCTs, one Q-RCT and five ITS). Findings on vending machines and grocery stores were not interpretable, and were rated as very low quality. A meta-analysis of the three RCTs, all of which assessed energy labelling on menus in restaurants, demonstrated a statistically significant reduction of 47 kcal in energy purchased (MD -46.72 kcal, 95% CI -78.35, -15.10, N = 1877). Assuming an average meal of 600 kcal, energy labelling on menus would reduce energy purchased per meal by 7.8% (95% CI 2.5% to 13.1%). The quality of the evidence for these three studies was rated as low, so our confidence in the effect estimate is limited and may change with further studies. Of the remaining six studies, only two (both ITS studies involving energy labels on menus or menus boards in a coffee shop or cafeteria) were at low risk of bias, and their results support the meta-analysis. The results of the other four studies which were conducted in a restaurant, cafeterias (2 studies) or a coffee shop, were not clearly reported and were at high risk of bias.Seventeen studies assessed the impact of nutritional labels on consumption in artificial settings or scenarios (henceforth referred to as laboratory studies or settings). Of these, eight (all RCTs) assessed the effect of labels on menus or placed on a range of food options. A meta-analysis of these studies did not conclusively demonstrate a reduction in energy consumed during a meal (MD -50 kcal, 95% CI -104.41, 3.88, N = 1705). We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies.Six laboratory studies (four RCTs and two Q-RCTs) assessed the impact of labelling a single food or drink option (such as chocolate, pasta or soft drinks) on energy consumed during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant difference in energy (kcal) consumed (SMD 0.05, 95% CI -0.17 to 0.27, N = 732). However, the confidence intervals were wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies.There was no evidence that nutritional labelling had the unintended harm of increasing energy purchased or consumed. Indirect evidence came from five laboratory studies that involved mislabelling single nutrient content (i.e. placing low energy or low fat labels on high-energy foods) during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant increase in energy (kcal) consumed (SMD 0.19, 95% CI -0.14to 0.51, N = 718). The effect was small and the confidence intervals wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence from these studies as very low, providing very little confidence in the effect estimate. AUTHORS' CONCLUSIONS: Findings from a small body of low-quality evidence suggest that nutritional labelling comprising energy information on menus may reduce energy purchased in restaurants. The evidence assessing the impact on consumption of energy information on menus or on a range of food options in laboratory settings suggests a similar effect to that observed for purchasing, although the evidence is less definite and also of low quality.Accordingly, and in the absence of observed harms, we tentatively suggest that nutritional labelling on menus in restaurants could be used as part of a wider set of measures to tackle obesity. Additional high-quality research in real-world settings is needed to enable more certain conclusions.Further high-quality research is also needed to address the dearth of evidence from grocery stores and vending machines and to assess potential moderators of the intervention effect, including socioeconomic status.
  • ItemPublished versionOpen Access
    The relationship between DXA-based and anthropometric measures of visceral fat and morbidity in women.
    (Springer Science and Business Media LLC, 2013-04-03) Direk, Kenan; Cecelja, Marina; Astle, William; Chowienczyk, Phil; Spector, Tim D; Falchi, Mario; Andrew, Toby; Astle, William [0000-0001-8866-6672]
    BACKGROUND: Excess accumulation of visceral fat is a prominent risk factor for cardiovascular and metabolic morbidity. While computed tomography (CT) is the gold standard to measure visceral adiposity, this is often not possible for large studies - thus valid, but less expensive and intrusive proxy measures of visceral fat are required such as dual-energy X-ray absorptiometry (DXA). Study aims were to a) identify a valid DXA-based measure of visceral adipose tissue (VAT), b) estimate VAT heritability and c) assess visceral fat association with morbidity in relation to body fat distribution. METHODS: A validation sample of 54 females measured for detailed body fat composition - assessed using CT, DXA and anthropometry - was used to evaluate previously published predictive models of CT-measured visceral fat. Based upon a validated model, we realised an out-of-sample estimate of abdominal VAT area for a study sample of 3457 female volunteer twins and estimated VAT area heritability using a classical twin study design. Regression and residuals analyses were used to assess the relationship between adiposity and morbidity. RESULTS: Published models applied to the validation sample explained >80% of the variance in CT-measured visceral fat. While CT visceral fat was best estimated using a linear regression for waist circumference, CT body cavity area and total abdominal fat (R2 = 0.91), anthropometric measures alone predicted VAT almost equally well (CT body cavity area and waist circumference, R2 = 0.86). Narrow sense VAT area heritability for the study sample was estimated to be 58% (95% CI: 51-66%) with a shared familial component of 24% (17-30%). VAT area is strongly associated with type 2 diabetes (T2D), hypertension (HT), subclinical atherosclerosis and liver function tests. In particular, VAT area is associated with T2D, HT and liver function (alanine transaminase) independent of DXA total abdominal fat and body mass index (BMI). CONCLUSIONS: DXA and anthropometric measures can be utilised to derive estimates of visceral fat as a reliable alternative to CT. Visceral fat is heritable and appears to mediate the association between body adiposity and morbidity. This observation is consistent with hypotheses that suggest excess visceral adiposity is causally related to cardiovascular and metabolic disease.
  • ItemAccepted versionOpen Access
    Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization.
    (Ovid Technologies (Wolters Kluwer Health), 2018-06) Zanetti, Daniela; Tikkanen, Emmi; Gustafsson, Stefan; Priest, James R; Burgess, Stephen; Ingelsson, Erik; Burgess, Stephen [0000-0001-5365-8760]
    BACKGROUND: Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies. METHODS: We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization. RESULTS: In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (β, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure. CONCLUSIONS: Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.
  • ItemPublished versionOpen Access
    Modal-based estimation via heterogeneity-penalized weighting: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid.
    (Oxford University Press (OUP), 2018-08-01) Burgess, Stephen; Zuber, Verena; Gkatzionis, Apostolos; Foley, Christopher N; Burgess, Stephen [0000-0001-5365-8760]; Zuber, Verena [0000-0001-9827-1877]; Foley, Christopher [0000-0002-0970-2610]
    BACKGROUND: A robust method for Mendelian randomization does not require all genetic variants to be valid instruments to give consistent estimates of a causal parameter. Several such methods have been developed, including a mode-based estimation method giving consistent estimates if a plurality of genetic variants are valid instruments; i.e. there is no larger subset of invalid instruments estimating the same causal parameter than the subset of valid instruments. METHODS: We here develop a model-averaging method that gives consistent estimates under the same 'plurality of valid instruments' assumption. The method considers a mixture distribution of estimates derived from each subset of genetic variants. The estimates are weighted such that subsets with more genetic variants receive more weight, unless variants in the subset have heterogeneous causal estimates, in which case that subset is severely down-weighted. The mode of this mixture distribution is the causal estimate. This heterogeneity-penalized model-averaging method has several technical advantages over the previously proposed mode-based estimation method. RESULTS: The heterogeneity-penalized model-averaging method outperformed the mode-based estimation in terms of efficiency and outperformed other robust methods in terms of Type 1 error rate in an extensive simulation analysis. The proposed method suggests two distinct mechanisms by which inflammation affects coronary heart disease risk, with subsets of variants suggesting both positive and negative causal effects. CONCLUSIONS: The heterogeneity-penalized model-averaging method is an additional robust method for Mendelian randomization with excellent theoretical and practical properties, and can reveal features in the data such as the presence of multiple causal mechanisms.
  • ItemPublished versionOpen Access
    (Elsevier BV, 2018) Ference, BA; Burgess, S; Staley, JR; Freitag, DF; Mason, AM; Nielsen, SF; Willeit, P; Young, R; Surendran, P; Karthikeyan, S; Bolton, TR; Peters, JE; Kamstrup, PR; Tybjaerg-Hansen, A; Benn, M; Langsted, A; Schnohr, P; Vedel-Krogh, S; Kobylecki, CJ; Ford, I; Packard, C; Trompet, S; Jukema, JW; Sattar, N; Di Angelantonio, E; Saleheen, D; Howson, JMM; Nordestgaard, BG; Butterworth, A; Danesh, J; Burgess, Stephen [0000-0001-5365-8760]; Mason, Amy [0000-0002-8019-0777]; Surendran, Praveen [0000-0002-4911-6077]; Karthikeyan, Savita [0000-0002-4798-5746]; Di Angelantonio, Emanuele [0000-0001-8776-6719]; Howson, Joanna [0000-0001-7618-0050]; Butterworth, Adam [0000-0002-6915-9015]; Danesh, John [0000-0003-1158-6791]
    Importance: Human genetic studies have indicated that plasma lipoprotein(a) [Lp(a)] is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) by 25-35% have not provided any evidence that lowering Lp(a) reduces CHD risk. Objective: To estimate the magnitude of the change in plasma Lp(a) needed to have the same effect on CHD risk as a 1 mmol/L (38.67 mg/dL) change in LDL-C, a change in LDL-C that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design: Meta-analysis of Mendelian randomization studies conducted using individual participant data from 5 studies; with external validation using summarized data from 48 studies. Setting: Population based prospective cohort and case-control studies. Participants: 20,793 CHD cases and 27,540 controls with individual participant data; 62,240 CHD cases and 127,299 controls with summarized data. Exposure: Genetic Lp(a) score and plasma Lp(a) mass concentration. Main outcomes and measures: Coronary heart disease. Results: The causal effect of Lp(a) on CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10 mg/dL lower genetically-predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR]: 0.942; 95% CI, 0.933–0.951; p=3×10-37), whereas a 10 mg/dL lower genetically-predicted LDL-C estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (0.855; 0.818–0.893; p=2×10-12). Thus, a 101.5 mg/dL (95% CI: 71.0–137.0) change in Lp(a) had the same effect on CHD risk as a 1 mmol/L change in LDL-C. The effect of Lp(a) on CHD risk appeared to be independent of changes in LDL-C due to genetic variants that mimic the effect of statins, PCSK9 inhibitors and ezetimibe. Conclusions and relevance: Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to a produce clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C by 1 mmol/L. Therefore, only people with very high plasma Lp(a) concentration are likely to derive a clinical benefit from therapies that lower Lp(a).
  • ItemAccepted versionOpen Access
    Serum 25-hydroxyvitamin D levels and risk of lung cancer and histologic types: a Mendelian randomisation analysis of the HUNT study.
    (European Respiratory Society (ERS), 2018-06) Sun, Yi-Qian; Brumpton, Ben M; Bonilla, Carolina; Lewis, Sarah J; Burgess, Stephen; Skorpen, Frank; Chen, Yue; Nilsen, Tom IL; Romundstad, Pål Richard; Mai, Xiao-Mei; Romundstad, Pål Richard [0000-0003-2061-4336]
    We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93-1.06) per allele score. A 25 nmol·L-1 increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54-1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study.
  • ItemPublished versionOpen Access
    Serum magnesium levels and risk of coronary artery disease: Mendelian randomisation study.
    (BioMed Central, 2018-05-17) Larsson, Susanna C; Burgess, Stephen; Michaëlsson, Karl; Larsson, Susanna C [0000-0003-0118-0341]; Burgess, Stephen [0000-0001-5365-8760]; Michaëlsson, Karl [0000-0003-2815-1217]
    Background. Observational studies have shown that serum magnesium levels are inversely associated risk of cardiovascular disease, but whether this association is causal is unknown. We conducted a Mendelian randomization study to investigate whether serum magnesium levels may be causally associated with coronary artery disease (CAD). Methods: This Mendelian randomization analysis is based on summary-level data from the CARDIoGRAMplusC4D consortium’s 1000 Genomes-based genome-wide association meta-analysis of 48 studies with a total 60,801 CAD cases and 123,504 non-cases. Six single nucleotide polymorphisms (SNPs) associated with serum magnesium levels at genome-wide significance were used as instrumental variables. Results: A genetic predisposition to higher serum magnesium levels was inversely associated with CAD. In conventional Mendelian randomization analysis, the odds ratio of CAD was 0.88 (95% confidence interval [CI]: 0.78 to 0.99; P = 0.03) per 0.1 mmol/L (about 1 standard deviation) increase in genetically predicted serum magnesium levels. Results were consistent in sensitivity analyses using the weighted median and heterogeneity-penalized model averaging methods, with odds ratios of 0.84 (95% CI: 0.72 to 0.98; P = 0.03) and 0.83 (95% CI: 0.71 to 0.96; P = 0.02), respectively. Conclusions: This study based on genetics provides evidence that serum magnesium levels are inversely associated with risk of CAD. Randomized controlled trials elucidating whether magnesium supplementation lowers the risk of CAD, preferably in a setting at higher risk of hypomagnesemia, are warranted.
  • ItemAccepted versionOpen Access
    Monthly vitamin D supplementation, pain, and pattern of analgesic prescription: secondary analysis from the randomized, double-blind, placebo-controlled Vitamin D Assessment study.
    (Ovid Technologies (Wolters Kluwer Health), 2018-06) Wu, Zhenqiang; Camargo, Carlos A; Malihi, Zarintaj; Bartley, Jim; Waayer, Debbie; Lawes, Carlene MM; Toop, Les; Khaw, Kay-Tee; Scragg, Robert; Khaw, Kay-Tee [0000-0002-8802-2903]
    Observational studies suggest that vitamin D deficiency is associated with higher risk of pain. However, evidence on the effect of vitamin D supplementation on pain is limited and contradictory. The aim of this study was to compare the effect of monthly high-dose vitamin D supplementation on a pain impact questionnaire (PIQ-6) score and prescription of analgesics in the general population. We performed a randomized, double-blind, placebo-controlled trial of 5108 community-dwelling participants, aged 50 to 84 years, who were randomly assigned to receive monthly 100,000-IU capsules of vitamin D3 (n = 2558) or placebo (n = 2550) for a median of 3.3 years. The PIQ-6 was administered at baseline, year 1, and final follow-up. Analgesic prescription data were collected from Ministry of Health. There was no difference in mean PIQ-6 score at the end of follow-up (adjusted mean difference: 0.06; P = 0.82) between the vitamin D (n = 2041) and placebo (n = 2014) participants. The proportion of participants dispensed one or more opioids was similar in the vitamin D group (n = 559, 21.9%) compared with placebo (n = 593, 23.3%); the relative risk (RR) adjusted for age, sex, and ethnicity was 0.94 (P = 0.24). Similar results were observed for dispensing of nonsteroidal anti-inflammatory drugs (RR = 0.94; P = 0.24) and other nonopioids (RR = 0.98; P = 0.34). Focusing on vitamin D deficient participants (<50 nmol/L, 24.9%), there was a lower risk of dispensing nonsteroidal anti-inflammatory drugs in the vitamin D group compared with placebo (RR = 0.87; P = 0.009); all other subgroup analyses were not significant. Long-term monthly high-dose vitamin D supplementation did not improve mean PIQ-6 score or reduce analgesic dispensing in the general population.
  • ItemPublished versionOpen Access
    Microinfarcts in an older population-representative brain donor cohort (MRC CFAS): Prevalence, relation to dementia and mobility, and implications for the evaluation of cerebral Small Vessel Disease.
    (Wiley, 2017-08) Ince, PG; Minett, T; Forster, G; Brayne, C; Wharton, SB; Medical Research Council Cognitive Function and Ageing Neuropathology Study; Soares Cianciarullo Minett, Thais [0000-0002-3232-9455]; Brayne, Carol [0000-0001-5307-663X]
    INTRODUCTION: Microinfarcts, small ischaemic foci common in ageing brain, are associated with dementia and gait dysfunction. We determined their relationship with dementia, mobility and cerebrovascular disease in an older population-representative brain donor cohort. These data on microinfarcts were evaluated in relation to pathological assessments of clinically significant cerebral small vessel disease (SVD). METHODS: Microinfarcts were assessed in the MRC Cognitive Function and Ageing Study (n = 331). Nine brain areas were staged according to the number of areas affected. RESULTS: 36% of brains showed at least 1 microinfarct. Higher cortical microinfarct stage was associated with dementia at death (OR 1.41, 95% CI 1.02; 1.96, P = 0.038), whilst cortical and subcortical microinfarct stages were associated with impaired mobility (OR 1.36, 95% CI 1.05-1.74; P 0.018) and falls (OR 1.96, 95% CI 1.11-3.43; P = 0.02). Adding data on microinfarcts to a definition of SVD, based on white matter lesions (WMLs), lacunes and significant arteriosclerosis, were assessed by comparing area under ROC curve (AUC) with and without microinfarcts. SVD was significantly related to dementia status with or without inclusion of microinfarcts. Modelling potential pathological definitions of SVD to predict dementia or impaired mobility indicated optimal prediction using combined assessment of WMLs, lacunes and microinfarcts. CONCLUSION: Cortical (dementia) and subcortical microinfarcts (impaired mobility) are related to diverse clinical outcomes. Optimal pathological assessment of significant SVD in brain ageing is achieved based on WMLs, lacunes and microinfarcts and may not require subjective assessment of the extent and severity of arteriosclerosis.
  • ItemPublished versionOpen Access
    Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology.
    (Wiley, 2016-02) Simpson, Julie E; Ince, Paul G; Minett, Thais; Matthews, Fiona E; Heath, Paul R; Shaw, Pamela J; Goodall, Emily; Garwood, Claire J; Ratcliffe, Laura E; Brayne, Carol; Rattray, Magnus; Wharton, Stephen B; MRC Cognitive Function and Ageing Neuropathology Study Group; Soares Cianciarullo Minett, Thais [0000-0002-3232-9455]; Matthews, Fiona [0000-0002-1728-2388]; Brayne, Carol [0000-0001-5307-663X]
    AIMS: Oxidative damage and an associated DNA damage response (DDR) are evident in mild cognitive impairment and early Alzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by Alzheimer-type pathology. METHODS: Frontal cortex (Braak stage 0-II) was obtained from the Medical Research Council's Cognitive Function and Ageing Study cohort. Neurones were isolated from eight cases (four high and four low DDR) by laser capture microdissection and changes in the transcriptome identified by microarray analysis. RESULTS: Two thousand three hundred seventy-eight genes were significantly differentially expressed (1690 up-regulated, 688 down-regulated, P < 0.001) in cases with a high neuronal DDR. Functional grouping identified dysregulation of cholesterol biosynthesis, insulin and Wnt signalling, and up-regulation of glycogen synthase kinase 3β. Candidate genes were validated by quantitative real-time polymerase chain reaction. Cerebrospinal fluid levels of 24(S)-hydroxycholesterol associated with neuronal DDR across all Braak stages (rs  = 0.30, P = 0.03). CONCLUSIONS: A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and Wnt signalling, and increased GSK3β, thereby contributing to neuronal dysfunction independent of Alzheimer-type pathology in the ageing brain.