ORCHIDS: an Observational Randomized Controlled Trial on Childhood Differential Susceptibility

A central tenet in developmental psychopathology is that childhood rearing experiences have a major impact on children’s development across life [1]. At the same time, we know that not all children are equally susceptible to these experiences [2]. Grounded in a diathesis-stress model, there has been growing attention for research on individuals’ genetic susceptibility to parenting. The diathesis-stress model holds that some children, due to a specific vulnerability, are more likely to be negatively affected by environmental risk, such as with parental harshness, than others [3‐5].

A typical characteristic of these studies is that they only examined environmental adversity and negative child outcomes. It may therefore be that we, for a long time, only studied so-called dandelions; the resilient children that do well even in the face of severe adversity [6]. In doing so, we may have overlooked the orchids; children who will suffer severely if ignored or maltreated, but flourish spectacularly when receiving adequate care. This metaphor forms the basis of an intriguing alternative hypothesis, namely the differential susceptibility hypothesis which holds that some children, due to a specific susceptibility factor, are more likely to be affected by environmental factors, for better and for worse[7, 8].

Preliminary evidence for this differential susceptibility hypothesis has accumulated over the past years. Previous studies demonstrated, for example, that children with the dopamine receptor D4 (DRD4) 7-repeat allele showed significantly more externalizing problem behavior when mothers were insensitive, but also showed less problem behavior when mothers were highly sensitive, compared to those without the DRD4 7-repeat allele [9]. Studies have identified several candidate genes underlying children’s differential susceptibility (e.g., monoamine oxidase A (MAOA) gene; dopamine transporter (DAT1) gene, dopamine receptor D4 (DRD4) gene, dopamine receptor D2 (DRD2) gene, serotonin-transporter (5-HTTLP-R) gene, and the catechol-o-methyltransferase (COMT) gene [10‐15].

However, the tenability of the genetic differential susceptibility hypothesis is still unclear, for several reasons. First, most previous studies only measured the presence or absence of environmental adversity and developmental problems, but not environmental enrichment and children’s competence. The absence of parental maltreatment, however, is not the same as parental warmth or sensitivity [16]. Only environmental conditions and outcomes ranging from dysfunction to competence make it possible to avoid ceiling effects in testing differential susceptibility [7, 17, 18]. Most importantly, most previous studies used correlational designs [19] and therefore alternative explanations for gene-environment (G × E) interactions cannot be ruled out. For example, children with oppositional behavior may be, genetically, more likely to evoke harsh parental discipline and to actively select environments that support their problem behavior.

Trials in which families are randomly distributed across different environmental conditions offer a solution to this problem [20, 21], because they permit a manipulation of the environment that is independent of children’s genetic makeup and developmental histories. To our knowledge four randomized controlled trials on G × E interactions in children’s social emotional development have been conducted so far [17, 22‐24].

These pioneering studies delivered important new insights, however their impact suffered from limitations as well. First, although the trials measured environmental enrichment the outcome was usually measured as a decrease in adolescent and child problem behavior, overlooking a possible increase in competent behavior. However, as argued above, to adequately examine differential susceptibility measurements of both environment and child behavior should range from dysfunction to competence. Second, the trials did not examine the possible underlying behavioral mechanism through which a G × E interaction may lead to different behavioral outcomes. It may be that carriers of candidate susceptibility genes show heightened behavioral reactivity. For example, children with low levels of dopaminergic functioning, associated with low reward sensitivity [25], may improve more during and after parent management training than those with high levels of dopaminergic functioning associated with high reward sensitivity, because they can benefit more from the individualization of use of rewards and extensive praising by parents. Likewise, children with decreased serotonergic functioning [25], associated with negative affect/mood, may improve strongly during and after parenting training due to the effect of an increase in positive parental emotions on this affect/mood. A highly reactive child will likely show an intense, mirroring emotional response to both negative and positive discipline [27, 28], which, in turn may lead to emotional synchronization in parent–child interactions. This congruency in affect may then lead to the development of either problem or prosocial behavior, depending on either positive or negative interactions with parents. Therefore, research should also investigate genetic expression “outside the skin”: the mechanisms through which genetic variation moderates the impact of environmental influences on individuals’ development. A randomized controlled trial can test hypotheses about underlying behavioral processes by examining whether certain mechanisms change in the experimental condition, mediating the intervention effect [29].

The ORCHIDS study described in this protocol is a genetically informed randomized controlled trial targeting families with children aged 4–8 who show mild to (sub)clinical behavior problems. The primary aim of ORCHIDS is to assess possible G × (G×)E interactions in the development of child behavior in its full scope – that is, from children’s problem behavior to their competencies. Our large scale randomized controlled trial is one of the first experimental studies of G × E interactions in social development. Experimental manipulation of the environment is crucial in understanding G × E interactions, because it is the only way to prevent confounding gene-environment covariation.

Additional to a single gene approach, we will investigate possible cumulative effects of multiple candidate genes (i.e., G × G × E or polygenetic interactions [46]). Also, we will make a first attempt to obtain more insight into the behavioral mechanism underlying these G × E interactions by examining (changes in) emotional synchronization in observed parent–child interactions.

Better insight into individual differences in, for example, reactivity to positive parenting behavior like praise, associated with dopaminergic and serotonergic functioning, may help improve the tailoring of behavioral parent training. This seems necessary as the mean effect size of these interventions is modest (Cohen’s d = 0.47 [47]). Individualization of use of rewards and praise may help increase the efficiency of these parenting skills. For example, if the emotional significance of the positive message of praise is less well processed, associated with altered dopaminergic functioning, both verbal and nonverbal enthusiasm may be particularly relevant for this specific subgroup of children [26]. Thus, instead of delivering interventions in a standardized way, parenting programs may benefit from an individualized approach based on insights from results of studies like the present one.

Despite the strengths and innovative aspects of ORCHIDS, there are some issues that our study is unable to take into account. Differential susceptibility to parenting may also be caused by environmental influences that alter the effects of genes (i.e., epigenetics), rather than by specific DNA sequences or a certain number of repeats alone [48]. Human development is an active process powered by a continuous interaction between the genome and the environment [49]. DNA methylation (i.e., the biochemical process that involves the addition of a methyl group onto cytosine in the DNA, regulating the operation of the human genome), for example, has been shown to mediate the relation between genotype and developmental outcomes [50, 51].

Once differential susceptibility to the environmental manipulations has been demonstrated, a next step will be to further investigate the behavioral as well as neurobiological underlying mechanisms of genetic differences in sensitivity to change. Interpreting the intervention effect in this study will be like looking at an “omnibus effect” that covers a variety of possible environmental effects or change mechanisms; the environmental change induced by the intervention consists of changes in many different parent behaviors and child responses. Which of these changes are driving the omnibus effect cannot be elucidated in a RCT. In order to create a more complete picture of gene-environment interplay, multiple genetically informed experimental designs should be used additionally to large scale RCT’s such as microtrials: small-scale, randomized experiments using a brief and focused environmental manipulation, designed to suppress specific risk mechanisms or enhance specific protective mechanisms but not to bring about full treatment or prevention effects in outcome [52].

The ORCHIDS study will investigate possible G × (G×)E interactions in the development of both positive and negative child behavior by assessing whether an experimental manipulation of the environment with the Incredible Years intervention is more effective for a particular genetic subgroup of children than for others. With this study we will contribute to a further understanding of moderating effects of specific alleles (i.e., polymorphisms) on the malleability of child behavior, and the behavioral mechanisms that may underlie gene-environment interactions. By doing so we gain more insight into what works for whom and how it works when it comes to interventions targeting child problem behavior.