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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration.
BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
Can cost-effectiveness results be combined into a coherent league table? Case study from one high-income country.
BACKGROUND: Doubts exist around the value of compiling league tables for cost-effectiveness results for health interventions, primarily due to methods differences. We aimed to determine if a reasonably coherent league table could be compiled using published studies for one high-income country: New Zealand (NZ). METHODS: Literature searches were conducted to identify NZ-relevant studies published in the peer-reviewed journal literature between 1 January 2010 and 8 October 2017. Only studies with the following metrics were included: cost per quality-adjusted life-year or disability-adjusted life-year or life-year (QALY/DALY/LY). Key study features were abstracted and a summary league table produced which classified the studies in terms of cost-effectiveness. RESULTS: A total of 21 cost-effectiveness studies which met the inclusion criteria were identified. There were some large methodological differences between the studies, particularly in the time horizon (1 year to lifetime) but also discount rates (range 0 to 10%). Nevertheless, we were able to group the incremental cost-effectiveness ratios (ICERs) into general categories of being reported as cost-saving (19%), cost-effective (71%), and not cost-effective (10%). The median ICER (adjusted to 2017 NZ$) was ~ $5000 per QALY/DALY/LY (~US$3500). However, for some interventions, there is high uncertainty around the intervention effectiveness and declining adherence over time. CONCLUSIONS: It seemed possible to produce a reasonably coherent league table for the ICER values from different studies (within broad groupings) in this high-income country. Most interventions were cost-effective and a fifth were cost-saving. Nevertheless, study methodologies did vary widely and researchers need to pay more attention to using standardised methods that allow their results to be included in future league tables.
Nutrient composition databases in the age of big data: foodDB, a comprehensive, real-time database infrastructure.
OBJECTIVES: Traditional methods for creating food composition tables struggle to cope with the large number of products and the rapid pace of change in the food and drink marketplace. This paper introduces foodDB, a big data approach to the analysis of this marketplace, and presents analyses illustrating its research potential. DESIGN: foodDB has been used to collect data weekly on all foods and drinks available on six major UK supermarket websites since November 2017. As of June 2018, foodDB has 3 193 171 observations of 128 283 distinct food and drink products measured at multiple timepoints. METHODS: Weekly extraction of nutrition and availability data of products was extracted from the webpages of the supermarket websites. This process was automated with a codebase written in Python. RESULTS: Analyses using a single weekly timepoint of 97 368 total products in March 2018 identified 2699 ready meals and pizzas, and showed that lower price ready meals had significantly lower levels of fat, saturates, sugar and salt (p<0.001). Longitudinal analyses of 903 pizzas revealed that 10.8% changed their nutritional formulation over 6 months, and 29.9% were either discontinued or new market entries. CONCLUSIONS: foodDB is a powerful new tool for monitoring the food and drink marketplace, the comprehensive sampling and granularity of collection provides power for revealing analyses of the relationship between nutritional quality and marketing of branded foods, timely observation of product reformulation and other changes to the food marketplace.
This paper gives the main findings of research designed to inform decisions about the format of a food selection guide, subsequently published as the National Food Guide. The research involved 2074 members of the public and 230 professionals involved in nutrition education. Different formats for the guide were assessed for performance (how well the information was understood and recalled) and preference with a quota sample of C2 and D socioeconomic groups. Preferences were also assessed with a sample of various professionals involved in nutrition education. The investigations involved different versions of the guide which varied in shape, background colour, presentational style (whether the foods depicted were many or few, photographic or drawn) and in the wording of the food group headings. The key findings were that exposure to a guide can have a significant effect on people's understanding of guide concepts and that some aspects of the design enhanced that effect. In particular, guides which were in the shape of a tilted plate were better at conveying nutritional concepts than those which were pyramid‐shaped. Members of the public and nutrition educators both preferred a plate shape but, whereas the public preferred a tilted plate to a flat plate, the nutrition educators thought that a flat plate would be more appealing to their clients than a tilted plate. Copyright © 1995, Wiley Blackwell. All rights reserved
The development of a National Food Guide for the United Kingdom is a priority in the action plans of the Nutrition Task Force. Pictorial food guides to translate nutrient recommendations into guidance for food choice have been in use in other parts of the world for many years. However, there has not, until the present time, been a nationally recognized guide in the United Kingdom. Such a tool would enable those involved in nutrition education programmes to address the public with consistent messages through a variety of different channels, thus reducing the potential for misinformation and misunderstanding. This paper describes a brief history of food guides, gives the background to the development of a guide in the United Kingdom and outlines the research and development process including consultation with a wide range of organizations. The development of dietetic and nutritional characteristics of the Guide format preferences and performance study results are described in accompanying papers in this issue on pages 323–334 and 335–351. Copyright © 1995, Wiley Blackwell. All rights reserved
BACKGROUND: Previous studies have shown a positive relationship between disease severity and cost. AIMS: To explore the factors affecting time to institutionalisation and estimate the relationship between the costs of care and disease progression. METHOD: Retrospective analysis of a longitudinal data-set for a cohort of 100 patients diagnosed with Alzheimer's disease or vascular dementia. RESULTS: Changes in both Mini-Mental State Examination (MMSE) and Barthel scores have independent and significant marginal effects on costs. Each one-point decline in the MMSE score is associated with a pound sterling 56 increase in the four-monthly costs, whereas each one-point fall in the Barthel index is associated with a pound sterling 586 increase in costs. CONCLUSIONS: It may be inappropriate for economic models of disease progression in dementia to be based solely on measures of cognitive change. MMSE and the Barthel index are independent significant predictors of time to institutionalisation and cost of care, but changes in the Barthel index are particularly important in predicting costs outside institutional care.
Lifetime effects, costs, and cost effectiveness of testing for human papillomavirus to manage low grade cytological abnormalities: results of the NHS pilot studies.
OBJECTIVES: To predict the incremental lifetime effects, costs, and cost effectiveness of using human papillomavirus testing to triage women with borderline or mildly dyskaryotic cervical smear results for immediate colposcopy. DESIGN: Modelling study. SETTING: Three centres participating in NHS pilot studies, United Kingdom. Population Women aged 25-64 with borderline or mildly dyskaryotic cervical smear results. INTERVENTIONS: Screening using conventional cytology, liquid based cytology, and four strategies with different age cut-off points and follow up times that used combined liquid based cytology and human papillomavirus testing (adjunctive human papillomavirus testing). RESULTS: The model predicts that compared with using conventional cytology without testing for human papillomavirus, testing for the virus in conjunction with liquid based cytology for women with borderline or mildly dyskaryotic cervical smear results (aged 35 or more) would cost 3735 pounds sterling (5528 euros; 6474 dollars) per life year saved. Extending adjunctive human papillomavirus testing in combination with liquid based cytology to include women aged between 25 and 34 costs an additional 4233 pounds sterling per life year saved. Human papillomavirus testing is likely to reduce lifetime repeat smears by 52%-86% but increase lifetime colposcopies by 64%-138%. CONCLUSIONS: Testing for human papillomavirus to manage all women with borderline or mildly dyskaryotic cervical smear results is likely to be cost effective. The predicted increase in lifetime colposcopies, however, deserves careful consideration.
Cost effectiveness of perindopril in reducing cardiovascular events in patients with stable coronary artery disease using data from the EUROPA study.
BACKGROUND: The EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) trial has recently reported. OBJECTIVE: To assess the cost effectiveness of perindopril in stable coronary heart disease in the UK. METHODS: Clinical and resource use data were taken from the EUROPA trial. Costs included drugs and hospitalisations. Health-related quality of life values were taken from published sources. A cost-effectiveness analysis is presented as a function of the risk of a primary event (non-fatal myocardial infarction, cardiac arrest or cardiovascular death) in order to identify people for whom treatment offers greatest value for money. RESULTS: The median incremental cost of perindopril for each quality-adjusted life year (QALY) gained across the heterogeneous population of EUROPA was estimated as 9700 pounds(interquartile range 6400-14,200 pounds). Overall, 88% of the EUROPA population had an estimated cost per QALY below 20,000 pounds and 97% below 30,000 pounds. For a threshold value of cost effectiveness of 30,000 pounds per QALY gained, treatment of people representing the 25th, 50th (median) and 75th centiles of the cost effectiveness distribution for perindopril has a probability of 0.999, 0.99 and 0.93 of being cost effective, respectively. Cost effectiveness was strongly related to higher risk of a primary event under standard care. CONCLUSIONS: Whether the use of perindopril can be considered cost effective depends on the threshold value of cost effectiveness of healthcare systems. For the large majority of patients included in EUROPA, the incremental cost per QALY gained was lower than the apparent threshold used by the National Institute for Health and Clinical Excellence in the UK.
PRIMEtime CE: a multistate life table model for estimating the cost-effectiveness of interventions affecting diet and physical activity.
BACKGROUND: Non-communicable diseases are the leading cause of death in England, and poor diet and physical inactivity are two of the principle behavioural risk factors. In the context of increasingly constrained financial resources, decision makers in England need to be able to compare the potential costs and health outcomes of different public health policies aimed at improving these risk factors in order to know where to invest so that they can maximise population health. This paper describes PRIMEtime CE, a multistate life table cost-effectiveness model that can directly compare interventions affecting multiple disease outcomes. METHODS: The multistate life table model, PRIMEtime Cost Effectiveness (PRIMEtime CE), is developed from the Preventable Risk Integrated ModEl (PRIME) and the PRIMEtime model. PRIMEtime CE uses routinely available data to estimate how changing diet and physical activity in England affects morbidity and mortality from heart disease, stroke, diabetes, liver disease, and cancers either directly or via raised blood pressure, cholesterol, and body weight. RESULTS: Model outcomes are change in quality adjusted life years, and change in English National Health Service and social care costs. CONCLUSION: This paper describes PRIMEtime CE and highlights its main strengths and limitations. The model can be used to compare any number of public policies affecting diet and physical activity, allowing decision makers to understand how they can maximise population health with limited financial resources.
Estimating the cost-effectiveness of salt reformulation and increasing access to leisure centres in England, with PRIMEtime CE model validation using the AdViSHE tool.
BACKGROUND: PRIMEtime CE is a multistate life table model that can directly compare the cost effectiveness of public health interventions affecting diet and physical activity levels, helping to inform decisions about how to spend finite resources. This paper estimates the costs and health outcomes in England of two scenarios: reformulating salt and expanding subsidised access to leisure centres. The results are used to help validate PRIMEtime CE, following the steps outlined in the Assessment of the Validation Status of Health-Economic decision models (AdViSHE) tool. METHODS: The PRIMEtime CE model estimates the difference in quality adjusted life years (QALYs) and difference in NHS and social care costs of modelled interventions compared with doing nothing. The salt reformulation scenario models how salt consumption would change if food producers met the 2017 UK Food Standards Agency salt reformulation targets. The leisure centre scenario models change in physical activity levels if the Birmingham Be Active scheme (where swimming pools and gym access is free to residents during defined periods) was rolled out across England. The AdViSHE tool was developed by health economic modellers and divides model validation into five parts: validation of the conceptual model, input data validation, validation of computerised model, operational validation, and other validation techniques. PRIMEtime CE is discussed in relation to each part. RESULTS: Salt reformulation was dominant compared with doing nothing, and had a 10-year return on investment of £1.44 (£0.50 to £2.94) for every £1 spent. By contrast, over 10 years the Be Active expansion would cost £727,000 (£514,000 to £1,064,000) per QALY. PRIMEtime CE has good face validity of its conceptual model and has robust input data. Cross-validation produces mixed results and shows the impact of model scope, input parameters, and model structure on cost-per-QALY estimates. CONCLUSIONS: This paper illustrates how PRIMEtime CE can be used to compare the cost-effectiveness of two different public health measures affecting diet and physical activity levels. The AdViSHE tool helps to validate PRIMEtime CE, identifies some of the key drivers of model estimates, and highlights the challenges of externally validating public health economic models against independent data.
Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium.
Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.
The resources available for healthcare are limited compared with demand, if not need, and all healthcare systems, regardless of their financing and organisation, employ mechanisms to ration or prioritise finite healthcare resources. This paper reviews alternative approaches that can be used to allocate healthcare resources. It discusses the problems encountered when allocating healthcare resources according to free market principles. It then proceeds to discuss the advantages and disadvantages of alternative resource allocation approaches that can be applied to public health systems. These include: (i) approaches based on the concept of meeting the needs of the population to maximising its capacity to benefit from interventions; (ii) economic approaches that identify the most efficient allocation of resources with the view of maximising health benefits or other measures of social welfare; (iii) approaches that seek to ration healthcare by age; and (iv) approaches that resolve resource allocation disputes through debate and bargaining. At present, there appears to be no consensus about the relative importance of the potentially conflicting principles that can be used to guide resource allocation decisions. It is concluded that whatever shape tomorrow's health service takes, the requirement to make equitable and efficient use of finite healthcare resources will remain.
The effectiveness of home versus community-based weight control programmes initiated soon after breast cancer diagnosis: a randomised controlled trial.
BACKGROUND: Breast cancer diagnosis may be a teachable moment for lifestyle behaviour change and to prevent adjuvant therapy associated weight gain. We assessed the acceptability and effectiveness of two weight control programmes initiated soon after breast cancer diagnosis to reduce weight amongst overweight or obese women and prevent gains in normal-weight women. METHODS: Overweight or obese (n = 243) and normal weight (n = 166) women were randomised to a three-month unsupervised home (home), a supervised community weight control programme (community) or to standard written advice (control). Primary end points were change in weight and body fat at 12 months. Secondary end points included change in insulin, cardiovascular risk markers, quality of life and cost-effectiveness of the programmes. RESULTS: Forty-three percent of eligible women were recruited. Both programmes reduced weight and body fat: home vs. control mean (95% CI); weight -2.3 (-3.5, -1.0) kg, body fat -1.6 (-2.6, -0.7) kg, community vs. control; weight -2.4 (-3.6, -1.1) kg, body fat -1.4 (-2.4, -0.5) kg (all p < 0.001). The community group increased physical activity, reduced insulin, cardiovascular disease risk markers, increased QOL and was cost-effective. CONCLUSIONS: The programmes were equally effective for weight control, but the community programme had additional benefits. CLINICAL TRIAL REGISTRATION: ISRCTN68576140.
Background: Some reports suggest that body mass index (BMI) is not strongly associated with mortality in Hispanic populations. Objective: To assess the causal relevance of adiposity to mortality in Mexican adults, avoiding reverse causality biases. Design: Prospective study. Setting: 2 Mexico City districts. Participants: 159 755 adults aged 35 years and older at recruitment, followed for up to 14 years. Participants with a hemoglobin A1c level of 7% or greater, diabetes, or other chronic diseases were excluded. Measurements: BMI, waist-to-hip ratio, waist circumference, and cause-specific mortality. Cox regression, adjusted for confounders, yielded mortality hazard ratios (HRs) after at least 5 years of follow-up and before age 75 years. Results: Among 115 400 participants aged 35 to <75 years at recruitment, mean BMI was 28.0 kg/m2 (SD, 4.1 kg/m2) in men and 29.6 kg/m2 (SD, 5.1 kg/m2) in women. The association of BMI at recruitment with all-cause mortality was J-shaped, with the minimum at 25 to <27.5 kg/m2. Above 25 kg/m2, each 5-kg/m2 increase in BMI was associated with a 30% increase in all-cause mortality (HR, 1.30 [95% CI, 1.24 to 1.36]). This association was stronger at ages 40 to <60 years (HR, 1.40 [CI, 1.30 to 1.49]) than at ages 60 to <75 years (HR, 1.24 [CI, 1.17 to 1.31]) but was not materially affected by sex, smoking, or other confounders. The associations of mortality with BMI and waist-to-hip ratio were similarly strong, and each was weakened only slightly by adjustment for the other. Waist circumference was strongly related to mortality and remained so even after adjustment for BMI and hip circumference. Limitations: Analyses were limited to mortality. Conclusion: General, and particularly abdominal, adiposity were strongly associated with mortality in this Mexican population. Primary Funding Source: Mexican Health Ministry, Mexican National Council of Science and Technology, Wellcome Trust, Medical Research Council, and Kidney Research UK.
Genetic Predisposition to Type 2 Diabetes and Risk of Subclinical Atherosclerosis and Cardiovascular Diseases Among 160,000 Chinese adults.
In observational studies, type 2 diabetes is associated with 2- to 4-fold higher risks of cardiovascular diseases (CVD). Using data from the China Kadoorie Biobank, we examined associations of genetically-predicted type 2 diabetes with CVD among ∼160,000 participants, to assess whether these relationships are causal. A type 2 diabetes genetic risk score (comprising 48 established risk variants) was associated with the presence of carotid plaque (OR 1.17 [95% CI 1.05, 1.29] per 1 unit higher log-odds of type 2 diabetes; n=6,819), and elevated risk of ischaemic stroke (IS) (1.08 [1.02, 1.14]; n=17,097), non-lacunar IS (1.09 [1.03, 1.16]; n=13,924) and major coronary event (1.12 [1.02, 1.23]; n= 5,081). There was no significant association with lacunar IS (1.03 [0.91, 1.16], n=3,173) or intracerebral haemorrhage (ICH) (1.01 [0.94, 1.10], n=6,973), although effect estimates were imprecise. These associations were consistent with observational associations of type 2 diabetes with CVD in CKB (p for heterogeneity>0.3), and with the associations of type 2 diabetes with IS, ICH and coronary heart disease in two-sample Mendelian randomisation analyses based on summary statistics from European population GWAS (p for heterogeneity>0.2). In conclusion, among Chinese adults, genetic predisposition to type 2 diabetes was associated with atherosclerotic CVD, consistent with a causal association.