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Translational Epidemiologic Approaches to Understanding the Consequences of Early-Life Exposures

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Abstract

Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes.

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References

  • Academy of Medical Sciences Working Group (2007) Identifying the environmental causes of disease: how should we decide what to believe and when to take action? Academy of Medical Sciences, London

    Google Scholar 

  • Allison PD (2009) Fixed effects regression models. Sage, Washington, DC

    Google Scholar 

  • Baker P, Mott FL (1989) NLSY child handbook. Center for Human Resource Research, Columbus

    Google Scholar 

  • Barker DJP (1998) Mothers, babies and health in later life, 2nd edn. Churchill Livingstone, Edinburgh

    Google Scholar 

  • Byrne N, Regan C, Howard L (2005) Administrative registers in psychiatric research: a systematic review of validity studies. Acta Psychiatr Scand 112:409–414

    Article  PubMed  Google Scholar 

  • Caspi A, Moffitt TE, Morgan J, Rutter M, Taylor A, Arseneault L, Tully L, Jacobs C, Kim-Cohen J, Polo-Tomas M (2004) Maternal expressed emotion predicts children’s antisocial behavior problems: using monozygotic-twin differences to identify environmental effects on behavioral development. Dev Psychol 40:149–161

    Article  PubMed  Google Scholar 

  • Chang Z, Lichtenstein P, D’Onofrio BM, Almqvist C, Kuja-Halkola R, Sjolander A, Larsson H (2014) Maternal age at childbirth and risk for ADHD in offspring: a population-based cohort study. Int J Epidemiol 43(6):1815–1824

    Article  PubMed Central  PubMed  Google Scholar 

  • Cicchetti D (1993) Developmental psychopathology: reactions reflections projections. Dev Rev 13:471–502

    Article  Google Scholar 

  • Coie JD, Watt NF, West SG, Hawkins JD, Asarnow JR, Markman HJ, Long B (1993) The science of prevention: a conceptual-framework and some directions for a national research-program. Am Psychol 48:1013–1022

    Article  PubMed  Google Scholar 

  • Coie JD, Miller-Jackson S, Bagwell C (2000) Prevention science. In: Sameroff AJ, Lewis M, Miller SM (eds) Handbook of developmental psychopathology, vol 2. Springer, New York, pp 94–114

    Google Scholar 

  • Cole SR, Hernan MA (2002) Fallibility in estimating direct effects. Int J Epidemiol 31(1):163–165

    Article  PubMed  Google Scholar 

  • Coley RL, Chase-Lansdale L (1998) Adolescent pregnancy and parenthood: recent evidence and future directions. Am Psychol 53(2):152–166

    Article  PubMed  Google Scholar 

  • Coyne CA, D’Onofrio BM (2012) Some (but not much) progress toward understanding teenage childbearing: a review of research in the past 10 years. Adv Child Dev Behav 42:113–152

    Article  PubMed Central  PubMed  Google Scholar 

  • Coyne CA, Långström N, Rickert ME, Lichtenstein P, D’Onofrio BM (2013) Maternal age at first birth and offspring criminality: using the children-of-twins design to test causal hypotheses. Dev Psychopathol 25:17–35

    Article  PubMed Central  PubMed  Google Scholar 

  • D’Onofrio BM, Turkheimer E, Eaves LJ, Corey LA, Berg K, Solaas MH, Emery RE (2003) The role of the children of twins design in elucidating causal relations between parent characteristics and child outcomes. J Child Psychol Psychiatry 44:1130–1144

    Article  PubMed  Google Scholar 

  • D’Onofrio BM, Van Hulle CA, Waldman ID, Rodgers JL, Harden KP, Rathouz PJ, Lahey BB (2008) Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds. Dev Psychopathol 20:139–164

    PubMed Central  PubMed  Google Scholar 

  • D’Onofrio BM, Lahey BB, Turkheimer E, Lichtenstein P (2013a) The critical need for family-based, quasi-experimental research in integrating genetic and social science research. Am J Public Health 103:S46–S55

    Article  PubMed Central  PubMed  Google Scholar 

  • D’Onofrio BM, Class QA, Rickert ME, Larsson H, Langstrom N, Lichtenstein P (2013b) Preterm birth and mortality and morbidity: a population-based quasi-experimental study. JAMA Psychiatry 70:1231–1240

    Article  PubMed  Google Scholar 

  • D’Onofrio BM, Class Q, Lahey B, Larsson H (2014) Testing the developmental origins of health and disease hypothesis for psychopathology using family-based, quasi-experimental designs. Child Dev Perspect 8(3):151–157. doi:10.1111/cdep.12078

    Article  PubMed Central  PubMed  Google Scholar 

  • Dick DM (2011) Gene-environment interaction in psychological traits and disorders. Annu Rev Clin Psychol 7:383–409

    Article  PubMed Central  PubMed  Google Scholar 

  • Donovan SJ, Susser E (2011) Commentary: advent of sibling designs. Int J Epidemiol 40:345–349

    Article  PubMed Central  PubMed  Google Scholar 

  • Eaves LJ, Silberg JL, Maes HH (2005) Revisiting the children of twins: can they be used to resolve the environmental effects of dyadic parental treatment on child behavior? Twin Res 8:283–290

    Google Scholar 

  • Eaves LJ, Pourcain BS, Smith GD, York TP, Evans DM (2014) Resolving the effects of maternal and offspring genotype on dyadic outcomes in genome wide complex trait analysis (“M-GCTA”). Behav Genet 44(5):445–455. doi:10.1007/s10519-014-9666-6

    Article  PubMed Central  PubMed  Google Scholar 

  • Fernando ABP, Robbins TW (2011) Animal models of neuropsychiatrics disorders. Annu Rev Clin Psychol 7:39–61

    Article  PubMed  Google Scholar 

  • Frisell T, Oberg S, Kuja-Halkola R, Sjolander A (2012) Sibling comparison designs: bias from non-shared confounders and measurement error. Epidemiology 23:713–720

    Article  PubMed  Google Scholar 

  • Ganzel BL, Morris PA (2011) Allostasis and the developing human brain: explicit considering of implicit models. Dev Psychopathol 23(4):955–974

    Article  PubMed  Google Scholar 

  • Gaziano JM (2010) The evolution of population science. JAMA 304(20):2288–2289. doi:10.1001/jama.2010.1691

    Article  PubMed  Google Scholar 

  • Greenland S, Pearl J, Robins JM (1999) Causal diagrams for epidemiologic research. Epidemiology 10(1):37–48

    Article  PubMed  Google Scholar 

  • Harden KP, Lynch SK, Turkheimer E, Emery RE, D’Onofrio BM, Slutske WS, Martin NG (2007) A behavior genetic investigation of adolescent motherhood and offspring mental health problems. J Abnorm Psychol 116:667–683

    Article  PubMed Central  PubMed  Google Scholar 

  • Heath AC, Kendler KS, Eaves LJ, Markell D (1985) The resolution of cultural and biological inheritance: informativeness of different relationships. Behav Genet 15:439–465

    Article  PubMed  Google Scholar 

  • Heckman JJ (2012) The developmental origins of health. Health Econ 21:24–29

    Article  PubMed Central  PubMed  Google Scholar 

  • Hiatt RA (2010) Invited commentary: the epicenter of translational science. Am J Epidemiol 172(5):525–527. doi:10.1093/aje/kwq212

    Article  PubMed  Google Scholar 

  • Jaffee S, Caspi A, Moffitt TE, Belsky JAY, Silva P (2001) Why are children born to teen mothers at risk for adverse outcomes in young adulthood? Results from a 20-year longitudinal study. Dev Psychopathol 13:377–397

    Article  PubMed  Google Scholar 

  • Jaffee SR, Price TS (2012) The implications of genotype–environment correlation for establishing causal processes in psychopathology. Dev Psychopathol 24((Special Issue 04)):1253–1264. doi:10.1017/S0954579412000685

    Article  PubMed  Google Scholar 

  • Kaufman JS, Maclehose RF, Kaufman S (2004) A further critique of the analytic strategy of adjusting for covariates to identify biologic mediation. Epidemiol Perspect Innov 1(1):4. doi:10.1186/1742-5573-1-4

    Article  PubMed Central  PubMed  Google Scholar 

  • Kendler KS, Baker JH (2007) Genetic influences on measures of the environment: a systematic review. Psychol Med 37:615–626

    Article  PubMed  Google Scholar 

  • Khoury MJ, Gwinn M, Ioannidis JPA (2010) The emergence of translational epidemiology: from scientific discovery to population health impact. Am J Epidemiol 172(5):517–524. doi:10.1093/aje/kwq211

    Article  PubMed Central  PubMed  Google Scholar 

  • Knopik VS (2009) Maternal smoking during pregnancy and child outcomes: real or spurious effect? Dev Neuropsychol 34:1–36

    Article  PubMed Central  PubMed  Google Scholar 

  • Knopik VS, Heath AC, Marceau K, Palmer RHC, McGeary JE, Todorov A, Evans AS (2015) Missouri Mothers and Their Children: a family study of the effects of genetics and the prenatal environment. Twin Res Hum Genet 18(05):485–496. doi:10.1017/thg.2015.46

    Article  PubMed Central  PubMed  Google Scholar 

  • Knudsen EI (2004) Sensitive periods in the development of the brain and behavior. J Cogn Neurosci 16(8):1412–1425

    Article  PubMed  Google Scholar 

  • Kuja-Halkola R, D’Onofrio BM, Illiadou A, Pawitan Y, Langstrom N, Lichtenstein P (2010) Prenatal smoking exposure and stress coping in late adolescence: no causal link. Int J Epidemiol 39:1531–1540

    Article  PubMed Central  PubMed  Google Scholar 

  • Kuja-Halkola R, D’Onofrio BM, Larsson H, Lichtenstein P (2014) Maternal smoking during pregnancy and adverse outcomes in offspring: genetic and environmental sources of covariance. Behav Genet 44(5):456–467. doi:10.1007/s10519-014-9668-4

    Article  PubMed Central  PubMed  Google Scholar 

  • Lahey BB, D’Onofrio BM (2010) All in the family: comparing siblings to test causal hypotheses regarding environmental influences on behavior. Curr Dir Psychol Sci 19:319–323

    Article  PubMed Central  PubMed  Google Scholar 

  • Lawlor DA, Mishra GD (2009) Family matters: designing, analysing, and understanding family-based studies in life course epidemiology. Oxford University Press, Oxford

    Book  Google Scholar 

  • Leve LD, Neiderhiser JM, Scaramella LV, Reiss D (2010) The early growth and development study: using the prospective adoption design to examine genotype-environment interplay. Behav Genet 40:306–314

    Article  PubMed  Google Scholar 

  • Light IJ (1973) The collaborative perinatal study of the national institute of neurological diseases and stroke: the women and their pregnancies. Am J Dis Child 125(1):146. doi:10.1001/archpedi.1973.04160010106025

    Google Scholar 

  • McAdams TA, Neiderhiser JM, Rijsdijk FV, Narusyte J, Lichtenstein P, Eley TC (2014) Accounting for genetic and environmental confounds in associations between parent and child characteristics: a systematic review of children-of-twins studies. Psychol Bull 140(4):1138–1173. doi:10.1037/a0036416

    Article  PubMed  Google Scholar 

  • McGue M, Osler M, Christensen K (2010) Causal inference and observational research: the utility of twins. Perspect Psychol Sci 5:546–556

    Article  PubMed Central  PubMed  Google Scholar 

  • Meyer KA, Williams P, Hernandez-Diaz S, Cnattingius S (2004) Smoking and risk of oral clefts: exploring the impact of study designs. Epidemiology 15:671–678

    Article  PubMed  Google Scholar 

  • Miettunen J, Suvisaari J, Haukka J, Isohanni M (2011) Use of register data for psychiatric epidemiology in the Nordic countries. In: Tsuang MT, Tohen M, Jones P (eds) Textbook of psychiatric epidemiology, 3rd edn. Wiley, Chichester, pp 117–131

    Chapter  Google Scholar 

  • Moffitt TE, Caspi A, Rutter M (2005) Strategy for investigating interactions between measured genes and measured environments. Arch Gen Psychiatry 62:473–481

    Article  PubMed  Google Scholar 

  • Neiderhiser JM, Reiss D, Hetherington EM (2007) The Nonshared Environment in Adolescent Development (NEAD) project: a longitudinal family study of twins and siblings from adolescence to young adulthood. Twin Res Hum Genet 10(1):74–83

    Article  PubMed  Google Scholar 

  • Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169

    Article  PubMed Central  PubMed  Google Scholar 

  • Parisi MA, Spong CY, Zajicek A, Guttmacher AE (2011) We don’t know what we don’t study: the case for research on medication effects in pregnancy. Am J Med Genet Part C 157(3):247–250. doi:10.1002/ajmg.c.30309

    Article  PubMed Central  Google Scholar 

  • Pearl J (2000) Causality: models, reasoning and inference. Cambridge University Press, Cambridge

    Google Scholar 

  • Pearl J (2001) Direct and indirect effects. In: Proceedings of the seventeenth conference on the uncertainty and artificial intelligence, Morgan Kaufman, San Fransisco, pp 411–420

  • Pechtel P, Pizzagalli D (2011) Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology 214(1):55–70. doi:10.1007/s00213-010-2009-2

    Article  PubMed Central  PubMed  Google Scholar 

  • Petersen L, Mortensen PB, Pedersen CB (2011) Paternal age at birth of first child and risk of schizophrenia. Am J Psychiatry 168:82–88

    Article  PubMed  Google Scholar 

  • Plomin R, Bergeman CS (1991) The nature of nurture: genetic influences on “environmental” measures. Behav Brain Sci 10:1–15

    Article  Google Scholar 

  • Plomin R, Daniels D (1987) Why are children in the same family so different from each other? Behav Brain Sci 10:1–16

    Article  Google Scholar 

  • Rice D, Barone S (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(3):511–533

    Article  PubMed Central  PubMed  Google Scholar 

  • Robins JM (2001) Data, design, and background knowledge in etiologic inference. Epidemiology 12(3):313–320

    Article  PubMed  Google Scholar 

  • Robins JM, Greenland S (1992) Identifiability and exchangeability for direct and indirect effects. Epidemiology 3(2):143–155

    Article  PubMed  Google Scholar 

  • Rutter M (2000) Psychosocial influences: critiques, findings, and research needs. Dev Psychopathol 12:375–405

    Article  PubMed  Google Scholar 

  • Rutter M (2007) Proceeding from observed correlation to causal inference: the use of natural experiments. Perspect Psychol Sci 2:377–395

    Article  PubMed  Google Scholar 

  • Rutter M, Silberg J, Simonoff E (1993) Whither behavior genetics? A developmental psychopathology perspective. In: Plomin R, McClearn GE (eds) Nature, nurture, and psychology. American Psychological Association, Washington, DC, pp 433–456

    Chapter  Google Scholar 

  • Rutter M, Pickles A, Murray R, Eaves LJ (2001) Testing hypotheses on specific environmental causal effects on behavior. Psychol Bull 127:291–324

    Article  PubMed  Google Scholar 

  • Shadish WR, Cook TD, Campbell DT (2002) Experimental and quasi-experimental designs for generalized causal inference. Houghton Mifflin, New York

    Google Scholar 

  • Silberg JL, Eaves LJ (2004) Analyzing the contribution of genes and parent-child interaction to childhood behavioral and emotional problems: a model for the children of twins. Psychol Med 34:347–356

    Article  PubMed  Google Scholar 

  • Sjolander A (2013) Reducing mean squared error in the analysis of binary paired data. Epidemiol Methods 2(1):33–47

    Google Scholar 

  • Sjölander A, Greenland S (2013) Ignoring the matching variables in cohort studies—when is it valid and why? Stat Med 32(27):4696–4708. doi:10.1002/sim.5879

    Article  PubMed  Google Scholar 

  • Sjolander A, Johansson ALV, Lundholm C, Altman D, Almqvist C, Pawitan Y (2012) Analysis of 1:1 matched cohort studies and twin studies, with binary exposures and binary outcomes. Stat Sci 27:395–411. doi:10.1214/12-STS390

    Article  Google Scholar 

  • Smith GD, Ebrahim S (2005) What can Mendelian randomization tell us about modifiable behavioural and environmental exposures? Br Med J 330:1076–1079

    Article  Google Scholar 

  • Susser E, Eide MG, Begg M (2010) Invited commentary: the use of sibship studies to detect familial confounding. Am J Epidemiol 172(5):537–539. doi:10.1093/aje/kwq196

    Article  PubMed  Google Scholar 

  • Thapar A, Rutter M (2009) Do prenatal risk factors cause psychiatric disorder? Be wary of causal claims. Br J Psychiatry 195:100–101

    Article  PubMed  Google Scholar 

  • Thapar A, Harold G, Rice F, Ge X, Boivin J, Hay D, Lewis A (2007) Do intrauterine or genetic influences explain the foetal origins of chronic disease? A novel experimental method for disentangling effects. BMC Med Res Methodol 7:25

    Article  PubMed Central  PubMed  Google Scholar 

  • Turkheimer E, Harden KP (2014) Behavior genetic research methods: testing quasi-causal hypotheses using multivariate twin data. In: Reis HT, Judd CM (eds) Handbook of research methods in personality and social psychology, 2nd edn. Cambridge University Press, Cambridge

    Google Scholar 

  • Turkheimer E, Waldron M (2000) Nonshared environment: a theoretical, methodological, and quantitative review. Psychol Bull 126(1):78–108

    Article  PubMed  Google Scholar 

  • Turley RNL (2003) Are children of young mothers disadvantaged because of their mother’s age or family background? Child Dev 74:465–474

    Article  PubMed  Google Scholar 

  • VanderWeele TJ (2009) Marginal structural models for the estimation of direct and indirect effects. Epidemiology 20(1):18–26. doi:10.1097/EDE.0b013e31818f69ce

    Article  PubMed  Google Scholar 

  • VanderWeele TJ (2010) Bias formulas for sensitivity analysis for direct and indirect effects. Epidemiology 21(4):540–551. doi:10.1097/EDE.0b013e3181df191c

    Article  PubMed Central  PubMed  Google Scholar 

  • VanderWeele TJ, Hernandez-Diaz S (2011) Is there a direct effect of pre-eclampsia on cerebral palsy not through preterm birth? Paediatr Perinat Epidemiol 25(2):111–115. doi:10.1111/j.1365-3016.2010.01175.x

    Article  PubMed  Google Scholar 

  • Vrieze SI, Iacono WG, McGue M (2012) Confluence of genes, environment, development, and behavior in a post Genome-Wide Association Study world. Dev Psychopathol 24:1195–1214

    Article  PubMed Central  PubMed  Google Scholar 

  • Weissman MM, Brown AS, Talati A (2011) Translational epidemiology in psychiatry: linking population to clinical and basic sciences. Arch Gen Psychiatry 68(6):600–608. doi:10.1001/archgenpsychiatry.2011.47

    Article  PubMed Central  PubMed  Google Scholar 

  • Zeanah CH, Gunnar MR, McCall RB, Kreppner JM, Fox NA (2011) Sensitive periods. Monogr Soc Res Child Dev 76(4):147–162

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We acknowledge financial support from the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM, Grant No. 340-2013-5867), NICHD (HD061817 and HD061384), and NIMH (MH094011 and MH102221).

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Authors and Affiliations

  1. Department of Psychological and Brain Sciences, Indiana University, 1101 E. 10th St., Bloomington, IN, 47405, USA

    Brian M. D’Onofrio, Quetzal A. Class, Martin E. Rickert & Ayesha C. Sujan

  2. Karolinska Institutet, Stockholm, Sweden

    Henrik Larsson, Ralf Kuja-Halkola, Arvid Sjölander, Catarina Almqvist, Paul Lichtenstein & A. Sara Oberg

  3. Harvard T.H. Chan School of Public Health, Boston, MA, USA

    A. Sara Oberg

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  1. Brian M. D’Onofrio
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  2. Quetzal A. Class
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  3. Martin E. Rickert
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  4. Ayesha C. Sujan
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  5. Henrik Larsson
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  6. Ralf Kuja-Halkola
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  8. Catarina Almqvist
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  9. Paul Lichtenstein
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  10. A. Sara Oberg
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Correspondence to Brian M. D’Onofrio.

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D’Onofrio, B.M., Class, Q.A., Rickert, M.E. et al. Translational Epidemiologic Approaches to Understanding the Consequences of Early-Life Exposures. Behav Genet 46, 315–328 (2016). https://doi.org/10.1007/s10519-015-9769-8

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