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1.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
doi:10.1093/ije/dys086
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
2.  Newly identified loci that influence lipid concentrations and risk of coronary artery disease 
Nature genetics  2008;40(2):161-169.
To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.
doi:10.1038/ng.76
PMCID: PMC5206900  PMID: 18193043
3.  Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence 
BMC Medicine  2016;14:205.
Background
Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood.
Methods
Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24–49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status.
Results
Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters.
Conclusions
Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0733-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0733-0
PMCID: PMC5153817  PMID: 27955712
Pregnancy; Trimesters; Postpartum; Metabolomics; Cytokines; Lipoprotein lipids; Fatty acids; Amino acids; Hormones; Inflammation; Metabolic networks
4.  Early Antenatal Prediction of Gestational Diabetes in Obese Women: Development of Prediction Tools for Targeted Intervention 
PLoS ONE  2016;11(12):e0167846.
All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0–18+6 weeks’ gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68–0.74). This increased to 0.77 (95%CI 0.73–0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74–0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most.
doi:10.1371/journal.pone.0167846
PMCID: PMC5145208  PMID: 27930697
5.  Long-term effects of the Active for Life Year 5 (AFLY5) school-based cluster-randomised controlled trial 
BMJ Open  2016;6(11):e010957.
Objective
To investigate the long-term effectiveness of a school-based intervention to improve physical activity and diet in children.
Design
Cluster-randomised controlled trial.
Setting
60 primary schools in the southwest of England.
Participants
Primary school children who were aged 8–9 years at recruitment, 9–10 years during the intervention and 10–11 years at the long-term follow-up assessment.
Intervention
Teacher training, provision of lesson and child–parent interactive homework plans and teaching materials.
Main outcome measures
Primary outcomes were accelerometer-assessed minutes of moderate to vigorous physical activity (MVPA) per day, accelerometer-assessed minutes of sedentary behaviour per day and reported daily consumption of servings of fruit and vegetables.
Results
60 schools with 2221 eligible children were recruited. As in the previously published assessment immediately after the end of the intervention, none of the three primary outcomes differed between children in schools allocated to the intervention, compared with those in control schools at the end of the long-term follow-up (1 year after the end of the intervention). Differences in secondary outcomes were consistent with those at the immediate follow-up, with no evidence that these had diminished over time. Comparing intervention with control schools, the difference in mean child-reported screen viewing at the weekend was −16.03 min (95% CI −32.82 to 0.73), for servings of snacks per day, the difference was −0.11 (95% CI −0.39 to 0.06), in servings of high-energy drinks per day −0.20 (95% CI −0.39 to −0.01) and in servings of high-fat foods per day −0.12 (95% CI −0.39 to 0.00). None of these reached our predefined level of statistical significance, especially after accounting for multiple testing.
Conclusions
School-based curriculum interventions alone are unlikely to have a major public health impact on children's diet and physical activity.
Trial registration number
ISRCTN50133740, Post-results.
doi:10.1136/bmjopen-2015-010957
PMCID: PMC5168509  PMID: 27884840
children; randomised controlled trial; schools; physical activity; diet
6.  Diagnostic performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using the SAF score as histological reference 
Summary
Background
Blood tests of liver injury are less well validated in non‐alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis.
Aims
To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading.
Methods
We pre‐included new NAFLD patients with biopsy and blood tests from a single‐centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary‐ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing.
Results
A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864–0.892) for FibroTest and fibrosis stages, 0.846 (0.830–0.862) for ActiTest and activity grades, and 0.822 (0.804–0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820–0.852; P = 0.0001), FIB4 (0.845; 0.829–0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850–0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05).
Conclusions
In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non‐invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis.
doi:10.1111/apt.13770
PMCID: PMC5113673  PMID: 27549244
7.  Loss to Follow-up in Cohort Studies 
Background
Although cohort members tend to be healthy and affluent compared with the whole population, some studies indicate this does not bias certain exposure-outcome associations. It is less clear whether this holds when socioeconomic position (SEP) is the exposure of interest.
Methods
As an illustrative example, we use data from the Avon Longitudinal Study of Parents and Children. We calculate estimates of maternal education inequalities in outcomes for which data are available on almost the whole cohort (birth weight and length, breastfeeding, preterm birth, maternal obesity, smoking during pregnancy, educational attainment). These are calculated for the full cohort (n~12,000) and in restricted subsamples defined by continued participation at age 10 years (n~7,000) and age 15 years (n~5,000).
Results
Loss to follow-up was related both to SEP and outcomes. For each outcome, loss to follow-up was associated with underestimation of inequality, which increased as participation rates decreased (eg, mean birth-weight difference between highest and lowest SEP was 116 g [95% confidence interval = 78 to 153] in the full sample and 93 g [45 to 141] and 62 g [5 to 119] in those attending at ages 10 and 15 years, respectively).
Conclusions
Considerable attrition from cohort studies may result in biased estimates of socioeconomic inequalities, and the degree of bias may worsen as participation rates decrease. However, even with considerable attrition (>50%), qualitative conclusions about the direction and approximate magnitude of inequalities did not change among most of our examples. The appropriate analysis approaches to alleviate bias depend on the missingness mechanism.
doi:10.1097/EDE.0b013e31827623b1
PMCID: PMC5102324  PMID: 23211345
8.  Socioeconomic disparities in trajectories of adiposity across childhood 
Background
Socioeconomic inequalities in obesity are consistently observed in high-income countries. The development of such inequalities across childhood; however, has not been studied using longitudinal data.
Methods
Using data from the Avon Longitudinal Study of Parents and Children (participants were born 1991/2 in South-West England), we modelled trajectories of ponderal index (PI) (N=12 246) from birth to 2 years and body mass index (BMI) (N=11 380) from 2 to 10 years. Individual trajectories were estimated using mixed-effects models, and differences in trajectories by socioeconomic position (measured by maternal education) were investigated.
Results
There was little socioeconomic patterning of PI from birth to 2 years. Socioeconomic differences in BMI began to emerge by 4 years old, and widened with increasing age. Amongst girls there was a clear gradient across all categories of maternal education by age 8, with daughters of more educated women being less adipose. Amongst boys, sons of degree-educated women had lower BMI but there was little difference between the lower maternal education categories. By 10 years old the mean BMI difference between the highest and lowest maternal education category was 0.38 kg/m2 for boys and 0.89 kg/m2 for girls. The results imply that interventions to prevent inequalities in childhood obesity should begin in pre-school years.
doi:10.3109/17477166.2010.500387
PMCID: PMC5102325  PMID: 20860432
Child; longitudinal studies; obesity; socioeconomic factors; ALSPAC
9.  Metabolic signatures of birthweight in 18 288 adolescents and adults 
Background: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults.
Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI).
Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood.
Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood.
doi:10.1093/ije/dyw255
PMCID: PMC5100627  PMID: 27892411
Fetal programming; metabolic signatures; metabolomics; adiposity; fatty acids; amino acids
10.  Hypertensive Disorders of Pregnancy and Offspring Cardiac Structure and Function in Adolescence 
Background
Fetal exposure to preeclampsia is associated with higher blood pressure and later risk of stroke. We aimed to investigate the associations of maternal preeclampsia, gestational hypertension, and maternal blood pressure change in pregnancy with offspring cardiac structure and function in adolescence.
Methods and Results
Using data from a prospective birth cohort study, we included offspring who underwent echocardiography (mean age, 17.7 years; SD, 0.3; N=1592). We examined whether hypertensive disorders of pregnancy were associated with offspring cardiac structure and systolic/diastolic function using linear regression. Using multilevel linear spline models (measurement occasions within women), we also investigated whether rate of maternal systolic/diastolic blood pressure change during pregnancy (weeks 8–18, 18–30, 30–36, and 36 or more) were associated with offspring outcomes. Main models were typically adjusted for maternal age, offspring age and sex, prepregnancy body mass index, parity, glycosuria/diabetes mellitus, education, and maternal smoking. Exposure to maternal preeclampsia (0.025; 95% CI, 0.008–0.043) and gestational hypertension (0.010; 0.002–0.017) were associated with greater relative wall thickness. Furthermore, preeclampsia was also associated with a smaller left ventricular end‐diastolic volume (−9.0 mL; −15 to −3.1). No associations were found between hypertensive disorders of pregnancy and offspring cardiac function. Positive rate of maternal systolic blood pressure change during weeks 8 to 18 was associated with greater offspring left ventricular end‐diastolic volume, left ventricular mass indexed to height2.7, and E/A.
Conclusions
Adolescent offspring exposed to maternal preeclampsia had greater relative wall thickness and reduced left ventricular end‐diastolic volume, which could be early signs of concentric remodeling and affect future cardiac function as well as risk of cardiovascular disease.
doi:10.1161/JAHA.116.003906
PMCID: PMC5210338  PMID: 27799232
ALSPAC; blood pressure; cohort study; concentric remodeling; echocardiography; epidemiology; hypertension; preeclampsia/pregnancy; Epidemiology; Primary Prevention; Pediatrics; Risk Factors; Remodeling
11.  Placental Size Is Associated Differentially With Postnatal Bone Size and Density 
Journal of Bone and Mineral Research  2016;31(10):1855-1864.
ABSTRACT
We investigated relationships between placental size and offspring adolescent bone indices using a population‐based, mother–offspring cohort. The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited pregnant women from the southwest of England between 1991 and 1993. There were 12,942 singleton babies born at term who survived at least the first 12 months. From these, 8933 placentas were preserved in formaldehyde, with maternal permission for their use in research studies. At the approximate age of 15.5 years, the children underwent a dual‐energy X‐ray absorptiometry (DXA) scan (measurements taken of the whole body minus head bone area [BA], bone mineral content [BMC], and areal bone mineral density [aBMD]). A peripheral quantitative computed tomography (pQCT) scan (Stratec XCT2000L; Stratec, Pforzheim, Germany) at the 50% tibial site was performed at this visit and at approximately age 17.7 years. In 2010 a sample of 1680 placentas were measured and photographed. To enable comparison of effect size across different variables, predictor and outcome variables were standardized to Z‐scores and therefore results may be interpreted as partial correlation coefficients. Complete placental, DXA, and pQCT data were available for 518 children at age 15.5 years. After adjustment for gender, gestational age at birth, and age at time of pQCT, the placental area was positively associated with endosteal circumference (β [95% CI]: 0.21 [0.13, 0.30], p < 0.001), periosteal circumference (β [95% CI]: 0.19 [0.10, 0.27], p < 0.001), and cortical area (β [95% CI]: 0.10 [0.01, 0.18], p = 0.03), and was negatively associated with cortical density (β [95% CI]: –0.11 [–0.20, –0.03], p = 0.01) at age 15.5 years. Similar relationships were observed for placental volume, and after adjustment for additional maternal and offspring covariates. These results suggest that previously observed associations between placental size and offspring bone development persist into older childhood, even during puberty, and that placental size is differentially related to bone size and volumetric density. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
doi:10.1002/jbmr.2840
PMCID: PMC5010780  PMID: 26999363
OSTEOPOROSIS; EPIDEMIOLOGY; PLACENTA; BONE MASS; DXA; pQCT; ASLPAC
12.  Exaggerated Exercise Blood Pressure is Associated with Higher Left Ventricular Mass in Adolescence. The Avon Longitudinal Study of Parents and Children 
Journal of hypertension  2016;34(Suppl 1):e55.
Objective
Dynamic exercise results in an increase to systolic blood pressure (BP). Irrespective of resting BP, some individuals may experience an exaggerated rise in systolic BP with exercise, which in adulthood, is associated with greater risk of developing hypertension, cardiovascular morbidity and mortality. It is not known if exercise BP is associated with adverse cardiovascular risk during adolescence. We determined associations of exercise BP with left ventricular mass (LVM) in adolescents, with consideration of the possible confounding effect of body composition.
Design and method
We undertook a cross-sectional study of 3,949 adolescents (mean age 17.8 ± 0.4 years, 45% male) who were part of a UK population-based birth cohort study. A sub-maximal exercise step-test with automated BP measurement immediately post-exercise was completed and body composition (total fat and lean mass) assessed by dual-energy x-ray absorptiometry. A sub-sample (n = 1,241) underwent comprehensive echocardiographic assessment.
Results
Each 5 mmHg increase in post-exercise systolic BP was associated with 0.34 g/m2.7 (95% CI: 0.24, 0.45) greater LVM indexed to height2.7 with adjustment for age, sex and hypertension status (p < 0.001). Further adjustment for lean mass attenuated this association to 0.29 g/m2.7 (95% CI 0.19, 0.39; p < 0.001) for each 5 mmHg of post-exercise systolic BP, adjustment for fat mass attenuated it to 0.15 g/m2.7 (95% CI 0.05, 0.25; p = 0.003), and adjustment for both lean and fat mass attenuated it to 0.13 g/m2.7 (95% CI 0.03, 0.23; p = 0.012). Individuals with post-exercise systolic BP ≥150 mmHg (corresponding to post-exercise systolic BP >70th percentile) had a 7% greater LVM compared to those with post-exercise systolic BP < 150 mmHg (p < 0.001).
Conclusions
Exaggerated exercise systolic BP is associated with higher LVM, adjustment for body composition attenuates but does not abolish this association. These results may have important implications for cardiovascular risk in later life
doi:10.1097/01.hjh.0000499992.80444.b7
PMCID: PMC5051632  PMID: 27753917
13.  Linear spline multilevel models for summarising childhood growth trajectories: A guide to their application using examples from five birth cohorts 
Childhood growth is of interest in medical research concerned with determinants and consequences of variation from healthy growth and development. Linear spline multilevel modelling is a useful approach for deriving individual summary measures of growth, which overcomes several data issues (co-linearity of repeat measures, the requirement for all individuals to be measured at the same ages and bias due to missing data). Here, we outline the application of this methodology to model individual trajectories of length/height and weight, drawing on examples from five cohorts from different generations and different geographical regions with varying levels of economic development. We describe the unique features of the data within each cohort that have implications for the application of linear spline multilevel models, for example, differences in the density and inter-individual variation in measurement occasions, and multiple sources of measurement with varying measurement error. After providing example Stata syntax and a suggested workflow for the implementation of linear spline multilevel models, we conclude with a discussion of the advantages and disadvantages of the linear spline approach compared with other growth modelling methods such as fractional polynomials, more complex spline functions and other non-linear models.
doi:10.1177/0962280213503925
PMCID: PMC4074455  PMID: 24108269
child; growth; height; longitudinal; multilevel models; spline; weight; ALSPAC; Born in Bradford; Generation XXI; Pelotas; PROBIT
14.  Cord Blood Adipokines and Lipids and Adolescent Nonalcoholic Fatty Liver Disease 
Context:
Maternal adiposity in pregnancy is associated with offspring adiposity and metabolic dysfunction postnatally, including greater risk of nonalcoholic fatty liver disease (NAFLD). Recent genetic analyses suggest a causal effect of greater maternal body mass index on offspring birth weight and ponderal index, but the relative roles of the environment in utero or later in life remains unclear.
Objective:
We sought to determine whether markers of infant adiposity (birth weight, umbilical cord blood leptin, adiponectin, and lipids) were associated with markers of NAFLD in adolescence.
Design, Setting, and Participants:
This was a UK prospective birth cohort with 17 years of follow-up with liver function tests (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase) (n = 1037 participants), and ultrasound scan assessed liver fat, volume, and sheer velocity at age 17 (n = 541 participants). Missing covariate data were imputed.
Main Outcomes:
Ultrasound and biochemical measures of NAFLD were measured.
Results:
Birth weight, cord blood leptin, and adiponectin were not associated with a diagnosis of NAFLD. In adjusted analyses, 2 of 42 associations attained conventional 5% levels of significance. Birth weight was positively associated with liver volume (1.0% greater per 100 g [95% confidence interval 0.5%–2.0%]). Cord high-density lipoprotein-cholesterol was positively associated with alanine aminotransferase (11.6% higher per 1 mmol/L [95% confidence interval 0.3, 23.4]); however, this association was primarily mediated via offspring adiposity.
Conclusions:
In this extensive analysis, we found little evidence measurements of infant fat mass and birth size were related to adolescent markers of NAFLD. The association between birth weight and adolescent liver volume may indicate the contribution of greater organ size to birth weight and tracking of organ size.
In a birth cohort of 1,037 children we found that there was no consistent evidence that birthweight, neonatal adiposity or umbilical cord lipids were associated with liver dysfunction in adolescence.
doi:10.1210/jc.2016-2604
PMCID: PMC5155695  PMID: 27648968
15.  Genetic evidence for causal relationships between maternal obesity-related traits and birth weight 
JAMA  2016;315(11):1129-1140.
Structured abstract
Importance
Neonates born to overweight/obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.
Objective
To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.
Design, Setting and Participants
We used Mendelian randomization to test whether maternal BMI and obesity-related traits are causally related to offspring birth weight. Mendelian randomization makes use of the fact that genotypes are randomly determined at conception and are thus not confounded by non-genetic factors. Data were analysed on 30,487 women from 18 studies. Participants were of European ancestry from population- or community-based studies located in Europe, North America or Australia and participating in the Early Growth Genetics (EGG) Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. We tested associations between a genetic score of 30 BMI-associated single nucleotide polymorphisms (SNPs) and (i) maternal BMI and (ii) birth weight, to estimate the causal relationship between BMI and birth weight. Analyses were repeated for other obesity-related traits.
Exposures
Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, HDL-cholesterol level, vitamin D status and adiponectin level.
Main Outcome(s) and Measure(s)
Offspring birth weight measured by trained study personnel (n=2 studies), from medical records (n= 10 studies) or from maternal report (n=6 studies).
Results
Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The genetic score for BMI was associated with a 2g (95%CI: 0, 3g) higher offspring birth weight per maternal BMI-raising allele (P=0.008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8g (95%CI: 6, 10g) per glucose-raising allele (P=7×10−14) and −4g (95%CI: −6, −2g) per SBP-raising allele (P=1×10−5), respectively. A 1 standard deviation (1 SD ≈ 4kg/m2) genetically higher maternal BMI was associated with a 55g (95% CI: 17, 93g) higher birth weight. A 1-SD genetically higher maternal fasting glucose (≈ 0.4mmol/L) or SBP (10mmHg) were associated with a 114g (95%CI: 80, 147g) higher or −208g (95% CI: −394, −21g) lower birth weight, respectively. For BMI and fasting glucose these genetic associations were consistent with the observational associations, but for SBP, the genetic and observational associations were in opposite directions.
Conclusions and Relevance
In this Mendelian randomization study of more than 30,000 women with singleton offspring from 18 studies, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal systolic blood pressure was shown to be potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
doi:10.1001/jama.2016.1975
PMCID: PMC4811305  PMID: 26978208
16.  Maternal preeclampsia is associated with reduced adolescent off-spring hip bone mineral density in a UK population based birth cohort 
Introduction
A suboptimal intrauterine environment has been postulated to have adverse long-term health effects, including an increased risk of osteoporosis. Since preeclampsia (PE) and to a lesser extent gestational hypertension (GH) are associated with impaired placental function we postulated that these represent hitherto unrecognised risk factors for reduced bone mineral density (BMD) of the offspring.
Objective
To investigate if exposure to PE or GH in utero is associated with BMD of the offspring as measured in late adolescence.
Methods
Mother-offspring pairs from the UK population based cohort study ALSPAC were investigated (N=3088 with relevant data). Multivariable linear regression was used to examine associations between PE/GH and total body, spine and total hip BMD at age 17.
Results
Of the 3088 mother-offspring pairs, 2% (n=60) of the mothers fulfilled criteria for PE and 14% (n=416) for GH. In confounder-adjusted analyses (ie age of scan, gender, maternal factors, including BMI, offspring height, fat and lean mass), PE was negatively associated with BMD at the hip (-0.30SD (-0.50, -0.10)) (SD difference (95% confidence interval)). This association was not attenuated by further adjustment for gestational age and birthweight, which were hypothesized to be on the causal pathway. There was also weak evidence for a negative association between PE and total body BMD (-0.17SD (-0.36, 0.02)), whereas no relationship was evident at the spine (-0.11SD (-0.30, 0.09)). In contrast, a positive association of GH with offspring total body, hip and spine BMD attenuated to the null with adjustment for confounders, in particular confounding via the maternal and offspring adiposity/size and the link between the two.
Conclusion
Modest negative associations from exposure to PE, but not GH may represent a hitherto unrecognised risk factor for low BMD. Further exploration of the causal relationship of the in utero environment on subsequent offspring bone health is required.
doi:10.1002/jbmr.2506
PMCID: PMC4540657  PMID: 25761963
Gestational hypertension; DXA; ALSPAC
17.  Effects of hormonal contraception on systemic metabolism: cross-sectional and longitudinal evidence 
Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood.
Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24–49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception.
Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery.
Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.
doi:10.1093/ije/dyw147
PMCID: PMC5100613  PMID: 27538888
hormonal contraception; combined oral contraceptive pills; progestin-only contraceptives; metabolomics; cytokines; inflammation; amino acids; fatty acids; lipoproteins; hormones; risk factors
18.  Born in Bradford’s Better Start: an experimental birth cohort study to evaluate the impact of early life interventions 
BMC Public Health  2016;16(1):711.
Background
Early interventions are recognised as key to improving life chances for children and reducing inequalities in health and well-being, however there is a paucity of high quality research into the effectiveness of interventions to address childhood health and development outcomes. Planning and implementing standalone RCTs for multiple, individual interventions would be slow, cumbersome and expensive. This paper describes the protocol for an innovative experimental birth cohort: Born in Bradford’s Better Start (BiBBS) that will simultaneously evaluate the impact of multiple early life interventions using efficient study designs. Better Start Bradford (BSB) has been allocated £49 million from the Big Lottery Fund to implement 22 interventions to improve outcomes for children aged 0–3 in three key areas: social and emotional development; communication and language development; and nutrition and obesity. The interventions will be implemented in three deprived and ethnically diverse inner city areas of Bradford.
Method
The BiBBS study aims to recruit 5000 babies, their mothers and their mothers’ partners over 5 years from January 2016-December 2020. Demographic and socioeconomic information, physical and mental health, lifestyle factors and biological samples will be collected during pregnancy. Parents and children will be linked to their routine health and local authority (including education) data throughout the children’s lives. Their participation in BSB interventions will also be tracked. BiBBS will test interventions using the Trials within Cohorts (TwiCs) approach and other quasi-experimental designs where TwiCs are neither feasible nor ethical, to evaluate these early life interventions. The effects of single interventions, and the cumulative effects of stacked (multiple) interventions on health and social outcomes during the critical early years will be measured.
Discussion
The focus of the BiBBS cohort is on intervention impact rather than observation. As far as we are aware BiBBS is the world’s first such experimental birth cohort study. While some risk factors for adverse health and social outcomes are increasingly well described, the solutions to tackling them remain elusive. The novel design of BiBBS can contribute much needed evidence to inform policy makers and practitioners about effective approaches to improve health and well-being for future generations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-3318-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-016-3318-0
PMCID: PMC4996273  PMID: 27488369
Birth cohort; Trials within cohort; Quasi-experimental; Inequalities; Early years interventions; Child health; Child development; Social; Emotional; Communication; Language; Obesity; Nutrition
19.  Role of Adiponectin in Coronary Heart Disease Risk 
Circulation Research  2016;119(3):491-499.
Supplemental Digital Content is available in the text.
Rationale:
Hypoadiponectinemia correlates with several coronary heart disease (CHD) risk factors. However, it is unknown whether adiponectin is causally implicated in CHD pathogenesis.
Objective:
We aimed to investigate the causal effect of adiponectin on CHD risk.
Methods and Results:
We undertook a Mendelian randomization study using data from genome-wide association studies consortia. We used the ADIPOGen consortium to identify genetic variants that could be used as instrumental variables for the effect of adiponectin. Data on the association of these genetic variants with CHD risk were obtained from CARDIoGRAM (22 233 CHD cases and 64 762 controls of European ancestry) and from CARDIoGRAMplusC4D Metabochip (63 746 cases and 130 681 controls; ≈ 91% of European ancestry) consortia. Data on the association of genetic variants with adiponectin levels and with CHD were combined to estimate the influence of blood adiponectin on CHD risk. In the conservative approach (restricted to using variants within the adiponectin gene as instrumental variables), each 1 U increase in log blood adiponectin concentration was associated with an odds ratio for CHD of 0.83 (95% confidence interval, 0.68–1.01) in CARDIoGRAM and 0.97 (95% confidence interval, 0.84–1.12) in CARDIoGRAMplusC4D Metabochip. Findings from the liberal approach (including variants in any locus across the genome) indicated a protective effect of adiponectin that was attenuated to the null after adjustment for known CHD predictors.
Conclusions:
Overall, our findings do not support a causal role of adiponectin levels in CHD pathogenesis.
doi:10.1161/CIRCRESAHA.116.308716
PMCID: PMC4959825  PMID: 27252388
adiponectin; cardiovascular disease; coronary artery disease; mendelian randomization analysis obesity
21.  Live-birth rate associated with repeat in vitro fertilisation treatment cycles 
JAMA  2015;314(24):2654-2662.
Importance
The likelihood of achieving a live-birth with repeat in-vitro fertilisation (IVF) is unclear, yet treatment is commonly limited to three or four embryo transfers.
Objective
To determine the live-birth rate per initiated IVF cycle and with repeated cycles.
Design, Setting and Participants
Prospective study of 156,947 UK women who received 257,398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed until June 2012.
Main exposure
IVF, with a cycle defined as an episode of ovarian stimulation and all subsequent separate fresh and frozen embryo transfers.
Main Outcome(s)
Live-birth rate per IVF cycle and the cumulative live-birth rates across all cycles in all women and by age and treatment type. Optimal, prognosis-adjusted and conservative cumulative live-birth rates were estimated, reflecting 0%, 30% and 100% of women discontinuing due to poor prognosis and having a live-birth rate of zero had they continued.
Results
In all women the live-birth rate for the first cycle was 29.5% (95%CI: 29.3, 29.7). This remained above 20% up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth, with 65.3% (64.8, 65.8) of women achieving a live-birth by the sixth cycle. In women younger than 40 using their own oocytes, the live-birth rate for the first cycle was 32.3% (32.0, 32.5), and remained above 20% up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68.4% (67.8, 68.9). For women aged 40-42, the live-birth rate for the first cycle was 12.3% (95%CI: 11.8, 12.8), with six cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5% (29.7, 33.3). For women older than 42 years all rates within each cycle were less than 4%. No age differential was observed among women using donor oocytes. Rates were lower in those with untreated male factor infertility compared to those with any other cause, but treatment with either intra-cytoplasmic sperm injection or sperm donation removed this difference.
Conclusions and relevance
Among women in the UK undergoing IVF, the cumulative prognosis-adjusted live-birth rate after six cycles was 65.3%, with variations by age and treatment type. These findings support the efficacy of extending the number of IVF cycles beyond three or four.
doi:10.1001/jama.2015.17296
PMCID: PMC4934614  PMID: 26717030
22.  Genome-wide association study of blood lead shows multiple associations near ALAD 
Human Molecular Genetics  2015;24(13):3871-3879.
Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993–1996 and 2002–2005 and from UK in 1991–1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10−14 for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10−6 > P > 5 × 10−8). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.
doi:10.1093/hmg/ddv112
PMCID: PMC4459389  PMID: 25820613
23.  Metabolic Characterization of a Rare Genetic Variation Within APOC3 and Its Lipoprotein Lipase–Independent Effects 
Supplemental Digital Content is available in the text.
Background—
Plasma triglyceride levels have been implicated in atherosclerosis and coronary heart disease. Apolipoprotein C-III (APOC3) plays a key role in the hydrolysis of triglyceride-rich lipoproteins to remnant particles by lipoprotein lipase (LPL) and their uptake by the liver. A rare variant in APOC3(rs138326449) has been associated with triglyceride, very low–density lipoprotein, and high-density lipoprotein levels, as well as risk of coronary heart disease. We aimed to characterize the impact of this locus across a broad set of mainly lipids-focused metabolic measures.
Methods and Results—
A high-throughput serum nuclear magnetic resonance metabolomics platform was used to quantify 225 metabolic measures in 13 285 participants from 2 European population cohorts. We analyzed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL-independent effects. Eighty-one metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported triglyceride and high-density lipoprotein associations, the variant was also associated with very low–density lipoprotein and high-density lipoprotein composition measures, other cholesterol measures, and fatty acids. Comparison of the APOC3 and LPL associations revealed that APOC3 association results for medium and very large very low–density lipoprotein composition are unlikely to be solely predictable by the action of APOC3 through LPL.
Conclusions—
We characterized the effects of the rare APOC3(rs138326449) loss of function mutation in lipoprotein metabolism, as well as the effects of LPL(rs12678919). Our results improve our understanding of the role of APOC3 in triglyceride metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.
doi:10.1161/CIRCGENETICS.115.001302
PMCID: PMC4920206  PMID: 27114411
association studies; genetics; lipids; LPL; metabolism; triglycerides; VLDL
24.  Sedentary Time in Late Childhood and Cardiometabolic Risk in Adolescence 
Pediatrics  2015;135(6):e1432-e1441.
BACKGROUND AND OBJECTIVE:
There is a paucity of prospective evidence examining the links between sedentary time (ST) and cardiometabolic outcomes in youth. We examined the associations between objectively assessed ST and moderate to vigorous physical activity (MVPA) in childhood with cardiometabolic risk in adolescence.
METHODS:
The study included 4639 children (47% male) aged 11 to 12 years at baseline whose mothers were enrolled in ALSPAC (Avon Longitudinal Study of Parents and Children) during their pregnancy in the early 1990s. A total of 2963 children had valid blood samples at age 15 to 16 years. Associations with baseline ST and MVPA were examined for BMI, waist circumference, body fat mass, lean body mass, systolic and diastolic blood pressure, fasting triglycerides, total cholesterol, low-density lipoprotein and high-density lipoprotein (HDL) cholesterol, glucose, insulin, C-reactive protein, and a clustered standardized cardiometabolic risk score (CMscore).
RESULTS:
Baseline ST was not associated deleteriously with any cardiometabolic markers. MVPA was beneficially associated with the 3 adiposity indicators, lean body mass, systolic blood pressure, triglycerides, C-reactive protein, insulin, HDL cholesterol, and CMscore; once the models were adjusted for baseline levels of these markers, these associations remained for body fat mass (mean difference per 10 minutes of MVPA: –0.320 [95% confidence interval (CI): –0.438 to –0.203]; P < .001), HDL cholesterol (0.006 logged mmol/L [95% CI: 0.001 to 0.011]; P = .028), insulin (–0.024 logged IU/L [95% CI: –0.036 to –0.013]; P < .001), and CMscore (–0.014 [95% CI: –0.025 to –0.004]; P = .009).
CONCLUSIONS:
We found no evidence linking ST in late childhood with adverse cardiometabolic outcomes in adolescence. Baseline MVPA was beneficially linked to broad cardiometabolic health in adolescence.
doi:10.1542/peds.2014-3750
PMCID: PMC4444802  PMID: 25986017
25.  Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomisation Meta-Analysis in the CARTA Consortium 
Background
Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.
Methods and Results
Data on 141,317 participants (62,666 never, 40,669 former, 37,982 current smokers) from 23 population-based studies were included in observational and Mendelian randomisation (MR) meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure (SBP, DBP), hypertension, and resting heart rate. For the MR analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower SBP, DBP, and lower hypertension risk, but with higher resting heart rate. In observational analyses amongst current smokers, one cigarette/day higher level of smoking heaviness was associated with higher (0.21 beats/minute; 95% CI 0.19; 0.24) resting heart rate, and slightly higher DBP (0.05 mmHg; 95% CI 0.02; 0.08) and SBP (0.08 mmHg; 95% CI 0.03; 0.13). However, in MR analyses amongst current smokers, while each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 beats/minute/allele; 95% CI 0.18; 0.54), there was no strong association with DBP, SBP, or hypertension. This would suggest a 7 beats/minute higher heart rate in those who smoke 20 cigarettes/day.
Conclusions
This MR meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
doi:10.1161/CIRCGENETICS.115.001225
PMCID: PMC4684098  PMID: 26538566
blood pressure; hypertension; Mendelian randomization; heart rate; smoking

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