Taurek, numbers and probabilities

In his paper, “Should the Numbers Count?" John Taurek imagines that we are in a position such that we can either save a group of five people, or we can save one individual, David. We cannot save David and the five. This is because they each require a life-saving drug. However, David needs all of the drug if he is to survive, while the other five need only a fifth each.Typically, people have argued as if there was a choice to be made: either numbers matter, in which case we should save the greater number, or numbers don't matter, but rather there is moral value in giving each person an equal chance of survival, and therefore we should toss a coin. My claim is that we do not have to make a choice in this way. Rather, numbers do matter, but it doesn't follow that we should always save the greater number. And likewise, there is moral value in giving each person an equal chance of survival, but it doesn't follow that we should always toss a coin.In addition, I argue that a similar approach can be applied to situations in which we can save one person or another, but the chances of success are different

Genome-wide association study identifies common and low-frequency variants at the AMHgene locus that strongly predict serum AMH levels in males

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 M ‘1000 Genomes Reference Panel’ imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (PMale = 2 × 10−49, Beta: ∼0.9 SDs per allele), rs8112524 (PMale = 3 × 10−8, Beta: ∼0.25)] and low-frequency variants [rs2385821 (PMale = 6 × 10−31, Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (PHet 0.0003–6.3 × 10−12), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men

The emergence of proton nuclear magnetic resonance metabolomics in the cardiovascular arena as viewed from a clinical perspective

The ability to phenotype metabolic profiles in serum has increased substantially in recent years with the advent of metabolomics. Metabolomics is the study of the metabolome, defined as those molecules with an atomic mass less than 1.5 kDa. There are two main metabolomics methods: mass spectrometry (MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy, each with its respective benefits and limitations. MS has greater sensitivity and so can detect many more metabolites. However, its cost (especially when heavy labelled internal standards are required for absolute quantitation) and quality control is sub-optimal for large cohorts. 1H NMR is less sensitive but sample preparation is generally faster and analysis times shorter, resulting in markedly lower analysis costs. 1H NMR is robust, reproducible and can provide absolute quantitation of many metabolites. Of particular relevance to cardio-metabolic disease is the ability of 1H NMR to provide detailed quantitative data on amino acids, fatty acids and other metabolites as well as lipoprotein subparticle concentrations and size. Early epidemiological studies suggest promise, however, this is an emerging field and more data is required before we can determine the clinical utility of these measures to improve disease prediction and treatment. This review describes the theoretical basis of 1H NMR; compares MS and 1H NMR and provides a tabular overview of recent 1H NMR-based research findings in the atherosclerosis field, describing the design and scope of studies conducted to date. 1H NMR metabolomics-CVD related research is emerging, however further large, robustly conducted prospective, genetic and intervention studies are needed to advance research on CVD risk prediction and to identify causal pathways amenable to intervention

Maternal thyroid function and child educational attainment: prospective cohort study

Objective: To determine if first trimester maternal thyroid dysfunction is a critical determinant of child scholastic performance and overall educational attainment. Design: Prospective cohort study. Setting: Avon Longitudinal Study of Parents and Children cohort in the UK. Participants: 4615 mother-child pairs with an available first trimester sample (median 10 weeks gestation, interquartile range 8-12). Exposures: Free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies assessed as continuous measures and the seven clinical categories of maternal thyroid function. Main outcome measures: Five age-specific national curriculum assessments in 3580 children at entry stage assessment at 54 months, increasing up to 4461 children at their final school assessment at age 15. Results: No strong evidence of clinically meaningful associations of first trimester free thyroxine and thyroid stimulating hormone levels with entry stage assessment score or Standard Assessment Test scores at any of the key stages was found. Associations of maternal free thyroxine or thyroid stimulating hormone with the total number of General Certificates of Secondary Education (GCSEs) passed (range 0-16) were all close to the null: free thyroxine, rate ratio per pmol/L 1.00 (95% confidence interval 1.00 to 1.01); and thyroid stimulating hormone, rate ratio 0.98 (0.94 to 1.02). No important relationship was observed when more detailed capped scores of GCSEs allowing for both the number and grade of pass or when language, mathematics, and science performance were examined individually or when all educational assessments undertaken by an individual from school entry to leaving were considered. 200 (4.3%) mothers were newly identified as having hypothyroidism or subclinical hypothyroidism and 97 (2.1%) subclinical hyperthyroidism or hyperthyroidism. Children of mothers with thyroid dysfunction attained an equivalent number of GCSEs and equivalent grades as children of mothers with euthyroidism. Conclusions: Maternal thyroid dysfunction in early pregnancy does not have a clinically important association with impaired child performance at school or educational achievement

Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts

Objectives: To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index. Design: Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index). Setting: Two large, prospective cohort studies in Denmark. Participants: We measured levels of uric acid and related covariables in 58 072 participants from the Copenhagen General Population Study and 10 602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively. Main outcome: Blood pressure and prospectively assessed ischaemic heart disease. Results: Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%). Conclusion: By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions

Preface to the special issue of Food and Chemical Toxicology on the outcomes of the MARLON project on veterinary epidemiology of potential health impacts of genetically modified feeds in livestock

peer-reviewedPreface to the special issue of Food and Chemical Toxicology on the outcomes of the MARLON project

Behavioural early-life exposures and body composition at age 15 years

BACKGROUND/OBJECTIVES: Previous studies have demonstrated associations between some early-life exposures and later obesity, but most have used body mass index in childhood or adulthood as the outcome. The objective of this study was to investigate whether early-life exposures were associated with directly measured fat and lean mass in adolescence. SUBJECTS/METHODS: This study used data on 4750 mother–offspring pairs, collected as a part of the Avon Longitudinal Study of Parents and Children, Bristol, UK between 1991 and 1992; associations between behavioural exposures occurring from conception up to 5 years of age (maternal and paternal smoking during pregnancy, breastfeeding, age at introduction to solids, dietary patterns and physical inactivity during early childhood) and offspring body composition measured by dual-energy X-ray absorptiometry at ~ 15 years were assessed. RESULTS: After full adjustment for potential confounders, maternal smoking during pregnancy, having a junk food diet and spending more time watching television in early childhood were all associated with higher fat mass at age 15, whereas maternal smoking, having a healthy diet and playing computer games more frequently in early childhood were all associated with a higher lean mass at age 15. Associations with paternal smoking were generally weaker for both fat and lean mass, but as there was no strong statistical evidence for maternal vs paternal differences, confounding by social factors rather than a direct effect of maternal smoking cannot be ruled out. Early feeding was not associated with fat or lean mass at age 15. CONCLUSIONS: This study does not provide compelling evidence for associations between most early-life factors and body composition in adolescence. However, possible associations with dietary patterns and physical inactivity in early childhood require further investigation in other cohorts that have direct measurements of adolescent body composition.SD Leary, DA Lawlor, G Davey Smith, MJ Brion and AR Nes

Intrauterine Growth and Intelligence Within Sibling Pairs: Findings From the Mater-University Study of Pregnancy and its Outcomes

Objective: To examine the association between intrauterine growth and intelligence. Design: Population based birth cohort study of sibling pairs born within a maximum of three years of each other. Setting: Mater-University women and children's hospital, Brisbane, Australia. Participants: 235 (470 children) sibling pairs. Results: Among one randomly selected sibling from each pair verbal comprehension at age 5, general intelligence at age 14, and reading ability at age 14 increased linearly with increasing gestational age and sex standardised birth weight z scores. With adjustment for maternal age, race, and smoking during pregnancy, birth order, family income, and parental education the associations with verbal comprehension at age 5 and general intelligence at age 14 remained, whereas the association with reading ability at age 14 was attenuated to the null. Within sibling pairs, differences in intrauterine growth were positively associated with differences in verbal comprehension at age 5 (test score difference per one unit difference in birth weight z score = 1.52 (0.11 to 3.26)) and general intelligence at age 14 (1.09 (0.01 to 2.18)), but not with reading ability at age 14. Conclusions: Socioeconomic position or other fixed maternal characteristics do not seem to explain the positive association between intrauterine growth and childhood intelligence

Use of soil moisture information in yield models

There are no author-identified significant results in this report