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    ABSTRACT: We hypothesised that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodelling such as cortical bone mineral density (BMDC ). CTX and mid-tibial pQCT scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass and height. CTX was positively related to PC [β= 0.19 (0.13, 0.24)] (coefficient = SD change per SD increase in CTX, 95% CI)], but inversely associated with BMDC [β= -0.46 (-0.52,-0.40)] and cortical thickness [β= -0.11 (-0.18, -0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) [β= 0.09 (0.03, 0.14)]. To examine the causal nature of this relationship, we then analysed whether SNPs within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding RANK, RANKL and OPG were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (P < 0.05 cut-off) (n = 2379). Subsequently, we performed a meta-analysis of associations between these SNPs and PC in ALSPAC (n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n = 938) and the Young Finns Study (YFS) (n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (P < 0.05 cut-off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2014; 29(4). DOI:10.1002/jbmr.2093
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    ABSTRACT: Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women's Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p=1.30x10⁻⁶), GCKR (rs1260326, p=1.63x10⁻⁶), ZNF259-APOA5 (rs651821, p=7.17x10⁻⁶) with plasma viscosity; andat CSF1 (rs333948, p=8.88x10⁻⁶) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16x10⁻⁷) and plasma viscosity (p=1.63x10⁻⁶), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00x10⁻²) and plasma viscosity (p<1.00x10⁻⁵). Triglyceride associated variants were overrepresented in factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci. In addition to confirming previously reported associations, we identified four single nucleotide polymorphisms (SNPs) associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation.
    Thrombosis and Haemostasis 10/2013; 110(5):995-1003. DOI:10.1160/TH13-02-0087
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    ABSTRACT: Within medical research there is an increasing trend toward deriving multiple types of data from the same individual. The most effective prognostic prediction methods should use all available data, since this maximizes the amount of information used. In this paper we consider a variety of learning strategies to boost prediction performance based on the use of all available data.Implementation: We consider data integration via the use of multiple kernel learning (MKL) supervised learning methods. We propose a scheme in which feature selection by statistical score is performed separately per data type and by pathway membership. We further consider the introduction of a confidence measure for the class assignment, both to remove some ambiguously labelled datapoints from the training data and to implement a cautious classifier which only makes predictions when the associated confidence is high. We use the METABRIC dataset (Curtis et al, 2012) for breast cancer, with prediction of survival at 2000 days from diagnosis. Predictive accuracy is improved by using kernels which exclusively use those genes, as features, which are known members of particular pathways. We show that yet further improvements can be made by using a range of additional kernels based on clinical covariates such as ER-status. Using this range of measures to improve prediction performance, we show that the test accuracy on new instances is nearly 80%, though predictions are only made on 69.2% of the patient cohort. J.Seoane@bristol.ac.uk.
    Bioinformatics 10/2013; 30(6). DOI:10.1093/bioinformatics/btt610
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    ABSTRACT: Lower maternal vitamin D status in pregnancy may be associated with increased offspring cardiovascular risk in later life, but evidence for this is scant. We examined associations of maternal total 25-hydroxyvitamin D (25(OH)D) in pregnancy with offspring cardiovascular risk factors assessed in childhood and adolescence. A longitudinal, prospective study. The study was based on data from mother-offspring pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective population-based birth cohort (N=4109). Offspring cardiovascular risk factors were measured in childhood (mean age 9.9 years) and in adolescence (mean age 15.4 years): blood pressure, lipids, apolipoproteins (at 9.9 years only), glucose and insulin (at 15.4 years only), C reactive protein (CRP), and interleukin 6 (at 9.9 years only) were measured. After adjustments for potential confounders (maternal age, education, body mass index (BMI), smoking, physical activity, parity, socioeconomic position, ethnicity, and offspring gestational age at 25(OH)D sampling; gender, age, and BMI at outcome assessment), maternal 25(OH)D was inversely associated with systolic blood pressure (-0.48 mm Hg difference per 50 nmol/L increase in 25(OH)D; 95% CI -0.95 to -0.01), Apo-B (-0.01 mg/dL difference; 95% CI -0.02 to -0.001), and CRP (-6.1% difference; 95% CI -11.5% to -0.3%) at age 9.9 years. These associations were not present for risk factors measured at 15.4 years, with the exception of a weak inverse association with CRP (-5.5% difference; 95% CI -11.4% to 0.8%). There was no strong evidence of associations with offspring triglycerides, glucose or insulin. Our findings suggest that fetal exposure to 25(OH)D is unlikely to influence cardiovascular risk factors of individuals later in life.
    Heart (British Cardiac Society) 10/2013; 99(24). DOI:10.1136/heartjnl-2013-303678
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    ABSTRACT: It has been suggested that maternal vitamin D status in pregnancy influences the risk of asthma and atopy in the offspring. The epidemiological evidence to support these claims is conflicting and may reflect chance findings and differences in how vitamin D was assessed. To examine the association between blood total maternal 25-hydroxy vitamin D (25(OH)D) concentrations in pregnancy and offspring asthma, atopy and lung function in the largest birth cohort study to date. Participants were largely of white European origin and resident in the South West of England. We examined the associations of maternal 25(OH)D concentrations in pregnancy with the following outcomes in the offspring: wheeze, asthma, atopy, eczema, hayfever, at mean age 7.5 years (n = 3652-4696 depending on outcome), IgE at 7 years (n = 2915) and lung function and bronchial responsiveness at mean age 8.7 years (n = 3728-3784). Sixty-eight per cent of mothers had sufficient (> 50 nmol/L) concentrations of 25(OH)D, 27% were insufficient (27.5-49.99 nmol/L) and 5% were deficient (< 27.5 nmol/L). There was no evidence to suggest that maternal 25(OH)D concentration in pregnancy was associated with any respiratory or atopic outcome in the offspring. These findings remained after adjustment for season of measurement and for potential confounders. There was also no evidence that these relationships followed a non-linear form and no evidence that either deficient or high concentrations of maternal 25(OH)D were associated with atopic or respiratory outcomes. We found no evidence that maternal blood 25(OH)D concentration in pregnancy is associated with childhood atopic or respiratory outcomes.
    Clinical & Experimental Allergy 10/2013; 43(10):1180-8. DOI:10.1111/cea.12172
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    ABSTRACT: To investigate whether physicians' prescribing preferences were valid instrumental variables for the antidepressant prescriptions they issued to their patients. We investigated whether physicians' previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom. Prior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.7 percentage points (95% CI, 26.7, 28.8) more likely to prescribe paroxetine, to their next patient. Physicians' previous prescriptions were less strongly associated with patients' baseline characteristics than actual prescriptions. We found no evidence that the estimated association of TCAs with self-harm/suicide using instrumental variable regression differed from conventional regression estimates (P-value = 0.45). The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants.
    Journal of clinical epidemiology 09/2013; 66(12). DOI:10.1016/j.jclinepi.2013.06.008
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    ABSTRACT: Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption we performed a population based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals respectively from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2,446,724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of fifteen independent loci, with ten loci reaching genome-wide significance (p<5x10(-8)) for 'age at first tooth' and eleven loci for 'number of teeth'. Together these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including a SNP in the protein-coding region of BMP4 (rs17563, P= 9.080x10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
    Human Molecular Genetics 09/2013; 22(18):3807-3817. DOI:10.1093/hmg/ddt231
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    ABSTRACT: An accumulating body of evidence suggests that offspring of mothers with preeclampsia have higher blood pressure during childhood and young adulthood compared with women without preeclampsia. However, the evidence with regard to offspring glucose metabolism and lipids is more scant. We examined whether maternal hypertensive disorders of pregnancy (preeclampsia and gestational hypertension) are associated with a range of cardiometabolic health measures in adolescent offspring. We included data for mother-offspring pairs from a United Kingdom prospective birth cohort (the Avon Longitudinal Study of Parents and Children). Repeat antenatal clinic measures of blood pressure and proteinuria (median 14 and 11, respectively) were used to ascertain maternal preeclampsia (n=53) and gestational hypertension (n=431). Offspring had blood pressure (n=4438), and fasting lipids, insulin, and glucose (n=2888) measured at a mean age of 17 years. There was no strong evidence of differences in fasting insulin, glucose, or lipid concentrations. Systolic and diastolic blood pressures were higher in offspring of mothers with gestational hypertension (mean difference, 2.06 mm Hg; 95% confidence interval, 1.28-2.84 and 1.11 mm Hg; 95% confidence interval, 0.54-1.69, respectively) and preeclampsia (1.12 mm Hg; 95% confidence interval, -0.89-3.12 and 1.71 mm Hg; 95% confidence interval, 0.23-3.17, respectively) compared with offspring of mothers without hypertensive disorders of pregnancy, adjusting for potential confounders (age, sex, maternal age at delivery, household social class, prepregnancy body mass index, parity, and smoking in pregnancy). Results suggest a specific association between maternal hypertensive disorders of pregnancy and offspring blood pressure that may be driven by genetics or familial nongenetic risk factors particular to blood pressure.
    Hypertension 08/2013; 62(3). DOI:10.1161/HYPERTENSIONAHA.113.01513
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    ABSTRACT: Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA) for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT). We quantified adiponectin from 3-mm diameter discs (≈3 µL of blood) punched from dried blood spots obtained from: i) whole blood standards (validation); and ii) PROBIT trial samples (application) in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose. In the validation study, mean intra-assay coefficients of variation (n = 162) were 15%, 13% and 10% for 'low' (6.78 µg/ml), 'medium' (18.18 µg/ml) and 'high' (33.13 µg/ml) internal quality control (IQC) samples, respectively; the respective inter-assay values (n = 40) were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93). Recovery of known quantities of adiponectin (between 4.5 to 36 µg/ml) was 100.3-133%. Bloodspot adiponectin was stable for at least 30 months at -80°C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96%) children. Mean adiponectin (standard deviation) concentrations were 17.34 µg/ml (7.54) in boys and 18.41 µg/ml (7.92) in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose. Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper and can be applied to large-scale studies.
    PLoS ONE 08/2013; 8(8):e71315. DOI:10.1371/journal.pone.0071315
  • International Journal of Epidemiology 08/2013; 42(4):1022-6. DOI:10.1093/ije/dyt105
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