Approaches for drawing causal inferences from epidemiological birth cohorts: A review

Early Human Development

Volumn 90, Issue 11, 2014, Pages 769-780

  Richmond, Rebecca C ^a   Al Amin, Aleef ^b   Davey Smith, George ^a   Relton, Caroline L ^a,c  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b UNIVERSITY OF BRISTOL   (United Kingdom)

^c NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Birth cohort; Causal inference; Consortia; DOHaD; Epidemiology; Epigenetics; Life course; Metabolomics; Omics

Indexed keywords

ADOLESCENCE; BIRTH; CHILDHOOD; EPIGENETICS; GENETICS; HUMAN; INFANCY; INSTRUMENTAL VARIABLE ANALYSIS; MENDELIAN RANDOMIZATION ANALYSIS; METABOLOMICS; PREGNANCY; PRENATAL EXPOSURE; PROGENY; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK FACTOR; SIBLING; TRIANGULATION; BIRTH RATE; COHORT ANALYSIS; EPIDEMIOLOGY; PROCEDURES;

BIRTH RATE; CAUSALITY; COHORT STUDIES; EPIGENOMICS; METABOLOMICS; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84908383904     PISSN: 03783782     EISSN: 18726232     Source Type: Journal    
DOI: 10.1016/j.earlhumdev.2014.08.023     Document Type: Review

References (126)

1. Gillman M.W. Developmental origins of health and disease. N Engl J Med 2005, 353:1848-1850.
2. Gluckman P., Me Hanson The developmental origins of health and disease 2006, Cambridge University Press, Cambridge.
3. Barker D.J. The fetal and infant origins of adult disease. BMJ 1990, 301:1111.
4. Barker D.J.P. Mothers, babies and disease in later life 1994, Churchill Livingstone, London.
5. Ong K.K., Ahmed M.L., Emmett P.M., Preece M.A., Dunger D.B. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 2000, 320:967-971.
6. Bergmann K.E., Bergmann R.L., Von Kries R., et al. Early determinants of childhood overweight and adiposity in a birth cohort study: role of breast-feeding. Int J Obes Relat Metab Disord 2003, 27:162-172.
7. Power C., Elliott J. Cohort profile: 1958 British birth cohort (National Child Development Study). Int J Epidemiol 2006, 35:34-41.
8. Ben-Shlomo Y., Kuh D. A life course approach to chronic disease epidemiology: conceptual models, empirical challenges and interdisciplinary perspectives. Int J Epidemiol 2002, 31:285-293.
9. Kuh D., Ben-Shlomo Y., Lynch J., Hallqvist J., Power C. Life course epidemiology. J Epidemiol Community Health 2003, 57:778-783.
10. Power C., Kuh D., Morton S. From developmental origins of adult disease to life course research on adult disease and aging: insights from birth cohort studies. Annu Rev Public Health 2013, 34:7-28.
11. Lawlor D.A., Ge Mishra Family Matters. Designing, analyzing and understanding family-based studies in life course epidemiology 2009, Oxford University Press, Oxford.
12. Vineis P., van Veldhoven K., Chadeau-Hyam M., Athersuch T.J. Advancing the application of omics-based biomarkers in environmental epidemiology. Environ Mol Mutagen 2013, 54:461-467.
13. Davey Smith G. Reflections on the limitations to epidemiology. J Clin Epidemiol 2001, 54:325-331.
14. Davey Smith G., Phillips A.N. Confounding in epidemiological studies: why "independent" effects may not be all they seem. BMJ 1992, 305:757-759.
15. Spratt M., Carpenter J., Sterne J.A., et al. Strategies for multiple imputation in longitudinal studies. Am J Epidemiol 2010, 172:478-487.
16. Tilling K., Davies N.M., Nicoli E., et al. Associations of growth trajectories in infancy and early childhood with later childhood outcomes. Am J Clin Nutr 2011, 94:1808S-1813S.
17. Fewell Z., Davey Smith G., Sterne J.A. The impact of residual and unmeasured confounding in epidemiologic studies: a simulation study. Am J Epidemiol 2007, 166:646-655.
18. Davey Smith G. Assessing intrauterine influences on offspring health outcomes: can epidemiological studies yield robust findings?. Basic Clin Pharmacol Toxicol 2008, 102:245-256.
19. Davey Smith G., Leary S., Ness A., Lawlor D.A. Challenges and novel approaches in the epidemiological study of early life influences on later disease. Adv Exp Med Biol 2009, 646:1-14.
20. Lawlor D.A., Davey Smith G., Kundu D., Bruckdorfer K.R., Ebrahim S. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence?. Lancet 2004, 363:1724-1727.
21. Mathews F., Yudkin P., Neil A. Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. BMJ 1999, 319:339-343.
22. Poston L., Briley A.L., Seed P.T., Kelly F.J., Shennan A.H. Vitamins in Pre-eclampsia Trial C. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006, 367:1145-1154.
23. Villar J., Purwar M., Merialdi M., et al. World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. BJOG Int J Obstet Gynaecol 2009, 116:780-788.
24. Roberts J.M., Myatt L., Spong C.Y., et al. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med 2010, 362:1282-1291.
25. Robinson S.M., Crozier S.R., Borland S.E., Hammond J., Barker D.J., Inskip H.M. Impact of educational attainment on the quality of young women's diets. Eur J Clin Nutr 2004, 58:1174-1180.
26. Mishra G., Nitsch D., Black S., De Stavola B., Kuh D., Hardy R. A structured approach to modelling the effects of binary exposure variables over the life course. Int J Epidemiol 2009, 38:528-537.
27. Kramer M.S., Chalmers B., Hodnett E.D., et al. Promotion of Breastfeeding Intervention Trial (PROBIT): a randomized trial in the Republic of Belarus. JAMA 2001, 285:413-420.
28. Patel R., Oken E., Bogdanovich N., et al. Cohort profile: the promotion of breastfeeding intervention trial (PROBIT). Int J Epidemiol 2014, 43:679-690.
29. Kramer M.S., Matush L., Vanilovich I., et al. Effects of prolonged and exclusive breastfeeding on child height, weight, adiposity, and blood pressure at age 6.5y: evidence from a large randomized trial. Am J Clin Nutr 2007, 86:1717-1721.
30. Martin R.M., Patel R., Kramer M.S., et al. Effects of promoting longer-term and exclusive breastfeeding on adiposity and insulin-like growth factor-I at age 11.5years: a randomized trial. JAMA 2013, 309:1005-1013.
31. Martin R.M., Patel R., Kramer M.S., et al. Effects of promoting longer-term and exclusive breastfeeding on cardiometabolic risk factors at age 11.5years: a cluster-randomized, controlled trial. Circulation 2014, 129:321-329.
32. Kramer M.S., Aboud F., Mironova E., et al. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry 2008, 65:578-584.
33. Skugarevsky O., Wade K.H., Richmond R.C., et al. Effects of promoting longer-term and exclusive breastfeeding on childhood eating attitudes: a cluster-randomized trial. Int J Epidemiol 2014, 43:1263-1271.
34. Brion M.J., Lawlor D.A., Matijasevich A., et al. What are the causal effects of breastfeeding on IQ, obesity and blood pressure? Evidence from comparing high-income with middle-income cohorts. Int J Epidemiol 2011, 40:670-680.
35. Lipsitch M., Tchetgen Tchetgen E., Cohen T. Negative controls: a tool for detecting confounding and bias in observational studies. Epidemiology 2010, 21:383-388.
36. Davey Smith G. Negative control exposures in epidemiologic studies. Epidemiology 2012, 23:350-351. [author reply 1-2].
37. Suren P., Roth C., Bresnahan M., et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 2013, 309:570-577.
38. Haberg S.E., Stigum H., Nystad W., Nafstad P. Effects of pre- and postnatal exposure to parental smoking on early childhood respiratory health. Am J Epidemiol 2007, 166:679-686.
39. Susser M., Stein Z. Timing in prenatal nutrition: a reprise of the Dutch Famine Study. Nutr Rev 1994, 52:84-94.
40. Lawlor D.A., Relton C., Sattar N., Nelson S.M. Maternal adiposity-a determinant of perinatal and offspring outcomes?. Nat Rev Endocrinol 2012, 8:679-688.
41. Lawlor D.A. The Society for Social Medicine John Pemberton Lecture 2011. Developmental overnutrition-an old hypothesis with new importance?. Int J Epidemiol 2013, 42:7-29.
42. Ebbeling C.B., Pawlak D.B., Ludwig D.S. Childhood obesity: public-health crisis, common sense cure. Lancet 2002, 360:473-482.
43. Whitaker R.C., Wright J.A., Pepe M.S., Seidel K.D., Dietz W.H. Predicting obesity in young adulthood from childhood and parental obesity. N Engl J Med 1997, 337:869-873.
44. Lawlor D.A., Davey Smith G., O'Callaghan M., et al. Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the mater-university study of pregnancy and its outcomes. Am J Epidemiol 2007, 165:418-424.
45. Lawlor D.A., Timpson N.J., Harbord R.M., et al. Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable. PLoS Med 2008, 5:e33.
46. Davey Smith G., Steer C., Leary S., Ness A. Is there an intrauterine influence on obesity? Evidence from parent child associations in the Avon Longitudinal Study of Parents and Children (ALSPAC). Arch Dis Child 2007, 92:876-880.
47. Kivimaki M., Lawlor D.A., Davey Smith G., et al. Substantial intergenerational increases in body mass index are not explained by the fetal overnutrition hypothesis: the Cardiovascular Risk in Young Finns Study. Am J Clin Nutr 2007, 86:1509-1514.
48. Patel R., Martin R.M., Kramer M.S., et al. Familial associations of adiposity: findings from a cross-sectional study of 12,181 parental-offspring trios from Belarus. PLoS One 2011, 6:e14607.
49. Fleten C., Nystad W., Stigum H., et al. Parent-offspring body mass index associations in the Norwegian Mother and Child Cohort Study: a family-based approach to studying the role of the intrauterine environment in childhood adiposity. Am J Epidemiol 2012, 176:83-92.
50. Vik K.L., Romundstad P., Carslake D., Davey Smith G., Nilsen T.I. Comparison of father-offspring and mother-offspring associations of cardiovascular risk factors: family linkage within the population-based HUNT Study, Norway. Int J Epidemiol 2014, 43:760-771.
51. Pembrey M.E., Bygren L.O., Kaati G., et al. Sex-specific, male-line transgenerational responses in humans. EJHG 2006, 14:159-166.
52. Northstone K., Golding J., Davey Smith G., Miller L.L., Pembrey M. Prepubertal start of father's smoking and increased body fat in his sons: further characterisation of paternal transgenerational responses. EJHG Apr. 2 2014, [Epub ahead of print]. 10.1038/ejhg.2014.31.
53. Davey Smith G. Epigenesis for epidemiologists: does evo-devo have implications for population health research and practice?. Int J Epidemiol 2012, 41:236-247.
54. Dabelea D., Hanson R.L., Lindsay R.S., et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000, 49:2208-2211.
55. Lawlor D.A., Lichtenstein P., Langstrom N. Association of maternal diabetes mellitus in pregnancy with offspring adiposity into early adulthood: sibling study in a prospective cohort of 280,866 men from 248,293 families. Circulation 2011, 123:258-265.
56. Lawlor D.A., Lichtenstein P., Fraser A., Langstrom N. Does maternal weight gain in pregnancy have long-term effects on offspring adiposity? A sibling study in a prospective cohort of 146,894 men from 136,050 families. Am J Clin Nutr 2011, 94:142-148.
57. Kral J.G., Biron S., Simard S., et al. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18years. Pediatrics 2006, 118:e1644-e1649.
58. Smith J., Cianflone K., Biron S., et al. Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity. J Clin Endocrinol Metabol 2009, 94:4275-4283.
59. Dodd J.M., Turnbull D.A., McPhee A.J., Wittert G., Crowther C.A., Robinson J.S. Limiting weight gain in overweight and obese women during pregnancy to improve health outcomes: the LIMIT randomised controlled trial. BMC Pregnancy Childbirth 2011, 11:79.
60. Briley A.L., Barr S., Badger S., et al. A complex intervention to improve pregnancy outcome in obese women; the UPBEAT randomised controlled trial. BMC Pregnancy Childbirth 2014, 14:74.
61. Shenkin S.D., Starr J.M., Deary I.J. Birth weight and cognitive ability in childhood: a systematic review. Psychol Bull 2004, 130:989-1013.
62. Lawlor D.A., Bor W., O'Callaghan M.J., Williams G.M., Najman J.M. Intrauterine growth and intelligence within sibling pairs: findings from the Mater-University study of pregnancy and its outcomes. J Epidemiol Community Health 2005, 59:279-282.
63. Matte T.D., Bresnahan M., Begg M.D., Susser E. Influence of variation in birth weight within normal range and within sibships on IQ at age 7 years: cohort study. BMJ 2001, 323:310-314.
64. Lawlor D.A., Clark H., Davey Smith G., Leon D.A. Intrauterine growth and intelligence within sibling pairs: findings from the Aberdeen children of the 1950s cohort. Pediatrics 2006, 117:e894-e902.
65. Yang S., Lynch J., Susser E.S., Lawlor D.A. Birth weight and cognitive ability in childhood among siblings and nonsiblings. Pediatrics 2008, 122:e350-e358.
66. Frisell T., Oberg S., Kuja-Halkola R., Sjolander A. Sibling comparison designs: bias from non-shared confounders and measurement error. Epidemiology 2012, 23:713-720.
67. Donovan S.J., Susser E. Commentary: advent of sibling designs. Int J Epidemiol 2011, 40:345-349.
68. Keyes K.M., Davey Smith G., Susser E. On sibling designs. Epidemiology 2013, 24:473-474.
69. Davey Smith G., Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol 2003, 32:1-22.
70. Davey Smith G., Ebrahim S. What can Mendelian randomisation tell us about modifiable behavioural and environmental exposures?. BMJ 2005, 330:1076-1079.
71. Davey Smith G., Lawlor D.A., Harbord R., Timpson N., Day I., Ebrahim S. Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology. PLoS Med 2007, 4:e352.
72. Davey Smith G. Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health. Genes Nutr 2011, 6:27-43.
73. Davey Smith G., Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 2004, 33:30-42.
74. Botto L.D., Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 2000, 151:862-877.
75. Czeizel A.E., Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992, 327:1832-1835.
76. Scholl T.O., Johnson W.G. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 2000, 71:1295S-1303S.
77. Davey Smith G., Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014, 23:R89-R98.
78. VanderWeele T.J., Tchetgen E.J.T., Cornelis M., Kraft P. Methodological challenges in Mendelian randomization. Epidemiology 2014, 25:427-435.
79. Didelez V., Sheehan N. Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res 2007, 16:309-330.
80. Lawlor D.A., Harbord R.M., Sterne J.A., Timpson N., Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008, 27:1133-1163.
81. Lawlor D.A., Davey Smith G., Mitchell R., Ebrahim S. Adult blood pressure and climate conditions in infancy: a test of the hypothesis that dehydration in infancy is associated with higher adult blood pressure. Am J Epidemiol 2006, 163:608-614.
82. Evans W.N., Ringel J.S. Can higher cigarette taxes improve birth outcomes?. J Public Econ 1999, 72:135-154.
83. Davey Smith G., Sterne J.A.C., Fraser A., Tynelius P., Lawlor D.A., Rasmussen F. The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study. Br Med J 2009, 339.
84. Carslake D., Fraser A., Davey Smith G., et al. Associations of mortality with own height using son's height as an instrumental variable. Econ Hum Biol 2013, 11:351-359.
85. Keyes K.M., Davey Smith G., Susser E. Commentary: smoking in pregnancy and offspring health: early insights into family-based and 'negative control' studies?. Int J Epidemiol 2014, [in press].
86. Lipton P. Inference to the Best Explanation 2004, Routledge, London. 2nd ed.
87. Govarts E., Nieuwenhuijsen M., Schoeters G., et al. Birth weight and prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE): a meta-analysis within 12 European Birth Cohorts. Environ Health Perspect 2012, 120:162-170.
88. Leventakou V., Roumeliotaki T., Martinez D., et al. Fish intake during pregnancy, fetal growth, and gestational length in 19 European birth cohort studies. Am J Clin Nutr 2014, 99:506-516.
89. Taal H.R., St Pourcain B., Thiering E., et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nat Genet 2012, 44:532-538.
90. Freathy R.M., Mook-Kanamori D.O., Sovio U., et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 2010, 42:430-435.
91. Bradfield J.P., Taal H.R., Timpson N.J., et al. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet 2012, 44:526-531.
92. Vrijheid M., Casas M., Bergstrom A., et al. European birth cohorts for environmental health research. Environ Health Perspect 2012, 120:29-37.
93. Larsen P.S., Kamper-Jorgensen M., Adamson A., et al. Pregnancy and birth cohort resources in Europe: a large opportunity for aetiological child health research. Paediatr Perinat Epidemiol 2013, 27:393-414.
94. Batty G.D., Alves J.G., Correia J., Lawlor D.A. Examining life-course influences on chronic disease: the importance of birth cohort studies from low- and middle- income countries. An overview. Braz J Med Biol Res 2007, 40:1277-1286.
95. Richter L.M., Victora C.G., Hallal P.C., et al. Cohort profile: the consortium of health-orientated research in transitioning societies. Int J Epidemiol 2012, 41:621-626.
96. Brion M.J., Zeegers M., Jaddoe V., et al. Intrauterine effects of maternal prepregnancy overweight on child cognition and behavior in 2 cohorts. Pediatrics 2011, 127:E202-E211.
97. Tyrrell J., Huikari V., Christie J.T., et al. Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight. Hum Mol Genet 2012, 21:5344-5358.
98. Eaves L., Pourcain B., Davey Smith G., York T., Evans D. Resolving the effects of maternal and offspring genotype on dyadic outcomes in genome wide complex trait analysis ("M-GCTA"). Behav Genet 2014, 1-11.
99. Palmer T.M., Lawlor D.A., Harbord R.M., et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res 2012, 21:223-242.
100. Burgess S., Thompson S.G. Use of allele scores as instrumental variables for Mendelian randomization. Int J Epidemiol 2013, 42:1134-1144.
101. Evans D.M., Brion M.J.A., Paternoster L., et al. Mining the human phenome using allelic scores that index biological intermediates. PLoS Genet 2013, 9.
102. Relton C.L., Davey Smith G. Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment. PLoS Med 2010, 7.
103. Relton C.L., Davey Smith G. Is epidemiology ready for epigenetics?. Int J Epidemiol 2012, 41:5-9.
104. Michels K.B. The promises and challenges of epigenetic epidemiology. Exp Gerontol 2010, 45:297-301.
105. Foley D.L., Craig J.M., Morley R., et al. Prospects for epigenetic epidemiology. Am J Epidemiol 2009, 169:389-400.
106. Ng J.W., Barrett L.M., Wong A., Kuh D., Davey Smith G., Relton C.L. The role of longitudinal cohort studies in epigenetic epidemiology: challenges and opportunities. Genome Biol 2012, 13:246.
107. Waterland R.A., Michels K.B. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007, 27:363-388.
108. Waterland R.A. Is epigenetics an important link between early life events and adult disease?. Horm Res 2009, 71:13-16.
109. Reynolds R.M., Jacobsen G.H., Drake A.J. What is the evidence in humans that DNA methylation changes link events in utero and later life disease?. Clin Endocrinol 2013, 78:814-822.
110. Heijmans B.T., Tobi E.W., Stein A.D., et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 2008, 105:17046-17049.
111. Joubert B.R., Haberg S.E., Nilsen R.M., et al. 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect 2012, 120:1425-1431.
112. Dominguez-Salas P., Moore S.E., Baker M.S., et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 2014, 5.
113. Godfrey K.M., Sheppard A., Gluckman P.D., et al. Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes 2011, 60:1528-1534.
114. Relton C.L., Groom A., St Pourcain B., et al. DNA methylation patterns in cord blood DNA and body size in childhood. PLoS One 2012, 7.
115. Groom A., Potter C., Swan D.C., et al. Postnatal growth and DNA methylation are associated with differential gene expression of the TACSTD2 gene and childhood fat mass. Diabetes 2012, 61:391-400.
116. Relton C.L., Davey Smith G. Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int J Epidemiol 2012, 41:161-176.
117. Kirkbride J.B., Susser E., Kundakovic M., Kresovich J.K., Davey Smith G., Relton C.L. Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects?. Epigenomics 2012, 4:303-315.
118. Joubert B.R., Haberg S.E., Bell D.A., et al. Maternal smoking and DNA methylation in newborns: in utero effect or epigenetic inheritance?. Cancer Epidemiol Biomarkers Prev 2014, 23:1007-1017.
119. Richmond R.C., Woodward G., Gaunt T.R., et al. Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) Unpublished at date of submission 2014.
120. Binder A.M., Michels K.B. The causal effect of red blood cell folate on genome-wide methylation in cord blood: a Mendelian randomization approach. BMC Bioinforma 2013, 14:353.
121. Ala-Korpela M., Kangas A.J., Soininen P. Quantitative high-throughput metabolomics: a new era in epidemiology and genetics. Genome Med 2012, 4:36.
122. Gieger C., Geistlinger L., Altmaier E., et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 2008, 4:e1000282.
123. Kettunen J., Tukiainen T., Sarin A.P., et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nat Genet 2012, 44:269-276.
124. Chadeau-Hyam M., Athersuch T.J., Keun H.C., et al. Meeting-in-the-middle using metabolic profiling-a strategy for the identification of intermediate biomarkers in cohort studies. Biomarkers 2011, 16:83-88.
125. Teslovich T.M., Musunuru K., Smith A.V., et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010, 466:707-713.
126. Roth C., Magnus P., Schjolberg S., et al. Folic acid supplements in pregnancy and severe language delay in children. JAMA 2011, 306:1566-1573.