Abstract
Genetically informed research on behavioral outcomes holds substantial promise for guiding efforts to enhance the efficacy and effectiveness of preventive interventions, but it also poses considerable challenges given the complexities of the dynamic interplay between genes and environment. This paper introduces a relatively uncommon research design, called microtrials, to provide a means of translating basic research findings into prevention trials, particularly through introducing genetic effects into prevention models. Microtrials are defined as randomized experiments testing the effects of relatively brief and focused environmental manipulations designed to suppress specific risk mechanisms or enhance specific protective mechanisms, but not to bring about full treatment or prevention effects in distal outcomes. Microtrial methods are described in detail, with discussion of their unique advantages for translating this knowledge base into prevention research. We end by raising several issues to consider when constructing genetically sensitive microtrials.
Similar content being viewed by others
References
Alexander, J. F., & Barton, C. (1980). Systems-behavioral intervention with delinquent families: Clinical, methodological, and conceptual considerations. In J. P. Vincent (Ed.), Advances in family intervention, assessment, and theory, volume 1. Greenwich, CT: JAI Press.
Bakermans-Kranenburg, J. M., Van Ijzendoorn, M. H., Pijlman, F. T. A., Mesman, J., & Juffer, F. (2008). Experimental evidence for differential susceptibility: Dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddlers’ externalizing behavior in a randomized controlled trial. Developmental Psychology, 44, 293–300.
Beach, S. R. H., Brody, G. H., Todorov, A., Gunter, T., & Philibert, R. A. (2010). Methylation at SLC6A4 is linked to family history of child abuse: An examination of the Iowa Adoptee Sample. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics, 153, 710–713.
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746–754.
Binder, E. B., Bradley, R. G., Liu, W., Epstein, M. P., Deveau, T. C., Mercer, K. B., et al. (2008). Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA: The Journal Of The American Medical Association, 299, 1291–1305.
Boyce, W. T., & Ellis, B. J. (2005). Biological sensitivity to context: I. An evolutionary-developmental theory of the origins and functions of stress reactivity. Development and Psychopathology, 17, 271–301.
Bradley, F. G., Rasellini, C., da Costa, M. A., Kowalski, T. F., Bloomental, A. B., Brown, M., et al. (2005). Gene silencing in the endocrine pancreas mediated by short-interfering RNA. Pancreas, 31, 373–379.
Brody, G. H., Beach, S. R. H., Philibert, R. A., Chen, Y., Lei, M., Murry, V. M., et al. (2009a). Parenting moderates a genetic vulnerability factor in longitudinal increases in youths’ substance use. Journal of Consulting and Clinical Psychology, 77, 1–12.
Brody, G. H., Beach, S. R. H., Philibert, R. A., Chen, Y., & Murry, V. M. (2009b). Prevention effects moderate the association of 5-HTTLPR and youth risk behavior initiation: Gene × environment hypotheses tested via a randomized prevention design. Child Development, 80, 645–661.
Brown, C. H., & Liao, J. (1999). Principles for designing randomized preventive trials in mental health: An emerging developmental epidemiology paradigm. American Journal of Community Psychology, 27, 673–710.
Canli, T., & Lesch, K.-P. (2007). Long story short: The serotonin transporter in emotion regulation and social cognition. Nature Neuroscience, 10, 1103–1109.
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301, 386–389.
Coie, J. D., Watt, N. F., West, S. G., Hawkins, J. D., Asarnow, J. R., Markman, H. J., et al. (1993). The science of prevention. A conceptual framework and some directions for a national research program. American Psychologist, 48, 1013–1022.
Conroy, J., Meally, E., Kearney, G., Firzgerald, M., Gill, M., & Gallagher, L. (2004). Serotonin transporter gene and autism: A haplotype analysis in an Irish autistic population. Molecular Psychiatry, 9, 587–593.
Degnan, K. A., & Fox, N. A. (2007). Behavioral inhibition and anxiety disorders: Multiple levels of a resilience process. Development and Psychopathology, 19, 729–746.
Dick, D. M., Viken, R., Purcell, S., Kaprio, J., Pulkkinen, L., & Rose, R. J. (2007). Parental monitoring moderates the importance of genetic and environmental influences on adolescent smoking. Journal of Abnormal Psychology, 116, 213–218.
Dumas, J. E., Gibson, J. A., & Albin, J. B. (1989). Behavioral correlates of maternal depressive symptomatology in conduct disordered children. Journal of Consulting and Clinical Psychology, 57, 516–521.
Feinn, R., Nellissery, M., & Kranzler, H. R. (2005). Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. American Journal of Medical Genetics, Part B, 133B, 79–84.
Fishbein, D. H., Hyde, C., Eldreth, D., Paschall, M. J., Hubal, R., Das, A., et al. (2006). Neurocognitive skills moderate urban male adolescents’ responses to preventive intervention materials. Drug and Alcohol Dependence, 82, 47–60.
Ge, X., Conger, R. D., Lorenz, F. O., & Elder, G. H. (1992). Linking family economic hardship to adolescent distress. Journal of Research on Adolescence, 2, 351–378.
Ge, X., Conger, R. D., Lorenz, F. O., Shanahan, M., & Elder, G. H., Jr. (1995). Mutual influences in parent and adolescent psychological distress. Developmental Psychology, 31, 406–419.
Gest, S. D., Mahoney, J. L., & Cairns, R. B. (1999). A developmental approach to prevention research: Configural antecedents of early parenthood. American Journal of Community Psychology, 27, 543–565.
Glover, V., Jaman, J., & Sandler, M. (1993). Migraine and depression: Biological aspects. Journal of Psychiatric Research, 27, 223–231.
Gottman, J., Ryan, K., Swanson, C., & Swanson, K. (2005). Proximal change experiments with couples: A methodology for empirically building a science of effective interventions for changing couples’ interaction. Journal of Family Communication, 5, 163–190.
Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science, 297, 400–403.
Hariri, A. R., Drabant, E. M., Munoz, K. E., Kolachana, B. S., Mattay, V. S., Egan, M. F., et al. (2005). A susceptibility gene for affective disorders and the response of the human amygdala. Archives of General Psychiatry, 62, 146–152.
Howe, G. W., Reiss, D., & Yuh, J. (2002). Can prevention trials test theories of etiology? Development and Psychopathology, 14, 673–694.
Jouriles, E. N., & Farris, A. (1992). Effects of marital conflict on subsequent parent-son interactions. Behavior Therapy, 23, 355–374.
Kaufman, J., Yand, B.-Z., Douglas-Palumberi, H., Grasso, D., Lipschitz, S. H., Krystal, J. H., et al. (2006). Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological Psychiatry, 59, 673–680.
Kendler, K. S., Kuhn, J. W., Vittum, J., Prescott, C. A., & Riley, B. (2005). The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: A replication. Archives of General Psychiatry, 62, 529–535.
Kim-Cohen, J., Caspi, A., Taylor, A., Williams, B., Newcombe, R., Craig, I. W., et al. (2006). MAOA, maltreatment, and gene-environment interaction predicting children’s mental health: New evidence and a meta-analysis. Molecular Psychiatry, 11, 903–913.
Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 1527–1531.
Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Feedman, A., et al. (1997). Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science, 277, 1659–1662.
Luthar, S. S. (2006). Resilience in development: A synthesis of research across five decades. In D. Cicchetti & D. J. Cohen (Eds.), Developmental psychopathology: Vol. 3. Risk, disorder, and adaptation (2nd ed., pp. 730–795). Hoboken, NJ: Wiley.
McClelland, G. H., & Judd, C. M. (1993). Statistical difficulties of detecting interactions and moderator effects. Psychological Bulletin, 1993, 376–390.
McGowan, P. O., Sasaki, A., D’Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., et al. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342–348.
Monroe, S. M., & Reid, M. W. (2009). Life stress and major depression. Current Directions in Psychological Science, 18, 68–72.
Mrazek, P. J., & Haggerty, R. J. (Eds.). (1994). Reducing risks for mental disorders. Frontiers for preventive intervention research (p. 16). Washington, DC: National Academic Press.
Narusyte, J., Neiderhiser, J. M., D’Onofrio, B. M., Reiss, D., Spotts, E. L., Ganiban, J., et al. (2008). Testing different types of genotype-environment correlation: An extended children-of-twins model. Developmental Psychology, 44, 1591–1603.
O’Connor, T. G., Deater-Deckard, K., Fulker, D., Rutter, M., & Plomin, R. (1998). Genotype-environment correlations in late childhood and early adolescence: Antisocial behavioral problems and coercive parenting. Developmental Psychology, 34, 970–981.
Philibert, R. A., Madan, A., Anderson, A., Cadoret, R., Packer, H., & Sandhu, H. (2007). Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 144B, 101–105.
Philibert, R. A., Sandhu, H., Hollenbeck, N., Gunter, T., Adams, W., & Madan, A. (2008). The relationship of 5HTT (SCL6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa adoption studies. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 543–549.
Plomin, R., Reiss, D., Hetherington, M. E., & Howe, G. W. (1994). Nature and nurture: Genetic contributions to measures of the family environment. Developmental Psychology, 30, 32–43.
Reiss, D., Neiderhiser, J., Hetherington, E. M., & Plomin, R. (2000). The relationship code: Deciphering genetic and social patterns in adolescent development. Cambridge, MA: Harvard University Press.
Risch, N., Herrell, R., Lehner, T., Liang, K. Y., Eaves, L., Hoh, J., et al. (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis. JAMA: The Journal Of The American Medical Association, 301, 2462–2471.
Shadish, W. R., Cook, T. D., & Campbell, D. T. (2002). Experimental and quasi-experimental designs for generalized causal inference. New York: Houghton Mifflin.
Suomi, S. J. (2009). How gene-environment interactions can influence the development of emotion regulation in rhesus monkeys. In S. L. Olson & A. J. Sameroff (Eds.), Biopsychosocial regulatory processes in the development of childhood behavioral problems (pp. 19–37). New York: Cambridge University Press.
Surtees, P. G., Wainwright, N. W. J., Willis-Owen, S. A. G., Luben, R., Day, N. E., & Flint, J. (2006). Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biological Psychiatry, 59, 224–229.
Uher, R., & McGuffin, P. (2008). The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: Review and methodological analysis. Molecular Psychiatry, 13, 131–146.
Webster-Stratton, C., & Hammond, M. (1990). Predictors of treatment outcome in parent-training for families with conduct problem children. Behavior Therapy, 21, 319–337.
Acknowledgement
Support for this article was provided in part by National Institute of Mental Health Grants R01MH073712 and 2R01MH040859, as well as by National Institute of Drug Abuse Grants DA010923, DA02173603, and 1P30DA027827–01.
We wish to express our appreciation to Peter Wyman, Hendricks Brown, and the Prevention Science and Methodology Group for their helpful discussion of these ideas.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Howe, G.W., Beach, S.R.H. & Brody, G.H. Microtrial Methods for Translating Gene-environment Dynamics into Preventive Interventions. Prev Sci 11, 343–354 (2010). https://doi.org/10.1007/s11121-010-0177-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11121-010-0177-2