Morgan Barak, Kumsta Robert, Fearon Pasco, Moser Dirk, Skeen Sarah, Cooper Peter, Murray Lynne, Moran Greg, Tomlinson Mark
Global Risk Governance Programme, Institute for Safety Goverance and Criminology, Law Faculty, University of Cape Town, Rondebosch, South Africa.
NRF Centre of Excellence in Human Development, DVC Research Office, University of Witwatersrand, Johannesburg, South Africa.
PLoS Med. 2017 Feb 28;14(2):e1002237. doi: 10.1371/journal.pmed.1002237. eCollection 2017 Feb.
Clear recognition of the damaging effects of poverty on early childhood development has fueled an interest in interventions aimed at mitigating these harmful consequences. Psychosocial interventions aimed at alleviating the negative impacts of poverty on children are frequently shown to be of benefit, but effect sizes are typically small to moderate. However, averaging outcomes over an entire sample, as is typically done, could underestimate efficacy because weaker effects on less susceptible individuals would dilute estimation of effects on those more disposed to respond. This study investigates whether a genetic polymorphism of the serotonin transporter gene moderates susceptibility to a psychosocial intervention.
We reanalyzed data from a randomized controlled trial of a home-visiting program delivered by community health workers in a black, isiXhosa-speaking population in Khayelitsha, South Africa. The intervention, designed to enhance maternal-infant attachment, began in the third trimester and continued until 6 mo postpartum. Implemented between April 1999 and February 2003, the intervention comprised 16 home visits delivered to 220 mother-infant dyads by specially trained community health workers. A control group of 229 mother-infant dyads did not receive the intervention. Security of maternal-infant attachment was the main outcome measured at infant age 18 mo. Compared to controls, infants in the intervention group were significantly more likely to be securely attached to their primary caregiver (odds ratio [OR] = 1.7, p = 0.029, 95% CI [1.06, 2.76], d = 0.29). After the trial, 162 intervention and 172 control group children were reenrolled in a follow-up study at 13 y of age (December 2012-June 2014). At this time, DNA collected from 279 children (134 intervention and 145 control) was genotyped for a common serotonin transporter polymorphism. There were both genetic data and attachment security data for 220 children (110 intervention and 110 control), of whom 40% (44 intervention and 45 control) carried at least one short allele of the serotonin transporter gene. For these 220 individuals, carrying at least one short allele of the serotonin transporter gene was associated with a 26% higher rate of attachment security relative to controls (OR = 3.86, p = 0.008, 95% CI [1.42, 10.51], d = 0.75), whereas there was a negligible (1%) difference in security between intervention and control group individuals carrying only the long allele (OR = 0.95, p = 0.89, 95% CI [0.45, 2.01], d = 0.03). Expressed in terms of absolute risk, for those with the short allele, the probability of secure attachment being observed in the intervention group was 84% (95% CI [73%, 95%]), compared to 58% (95% CI [43%, 72%]) in the control group. For those with two copies of the long allele, 70% (95% CI [59%, 81%]) were secure in the intervention group, compared to 71% (95% CI [60%, 82%]) of infants in the control group. Controlling for sex, maternal genotype, and indices of socioeconomic adversity (housing, employment, education, electricity, water) did not change these results. A limitation of this study is that we were only able to reenroll 49% of the original sample randomized to the intervention and control conditions. Attribution of the primary outcome to causal effects of intervention in the present subsample should therefore be treated with caution.
When infant genotype for serotonin transporter polymorphism was taken into account, the effect size of a maternal-infant attachment intervention targeting impoverished pregnant women increased more than 2.5-fold when only short allele carriers were considered (from d = 0.29 for all individuals irrespective of genotype to d = 0.75) and decreased 10-fold when only those carrying two copies of the long allele were considered (from d = 0.29 for all individuals to d = 0.03). Genetic differential susceptibility means that averaging across all participants is a misleading index of efficacy. The study raises questions about how policy-makers deal with the challenge of balancing equity (equal treatment for all) and efficacy (treating only those whose genes render them likely to benefit) when implementing psychosocial interventions.
Current Controlled Trials ISRCTN25664149.
对贫困对儿童早期发育的有害影响的清晰认识激发了人们对旨在减轻这些有害后果的干预措施的兴趣。旨在减轻贫困对儿童负面影响的心理社会干预措施经常被证明是有益的，但效应大小通常较小到中等。然而，像通常那样对整个样本的结果进行平均可能会低估疗效，因为对较不易受影响个体的较弱效应会稀释对那些更易产生反应个体的效应估计。本研究调查血清素转运体基因的一种基因多态性是否会调节对心理社会干预的易感性。
我们重新分析了一项随机对照试验的数据，该试验是在南非开普敦Khayelitsha一个讲科萨语的黑人社区中由社区卫生工作者实施的家访项目。该干预旨在增强母婴依恋，从孕晚期开始，持续到产后6个月。该干预在1999年4月至2003年2月期间实施，由经过专门培训的社区卫生工作者对220对母婴进行了16次家访。229对母婴组成的对照组未接受干预。母婴依恋安全性是在婴儿18个月大时测量的主要结果。与对照组相比，干预组的婴儿与主要照料者形成安全依恋的可能性显著更高（优势比[OR]=1.7，p = 0.029，95%置信区间[1.06, 2.76]，d = 0.29）。试验结束后，162名干预组儿童和172名对照组儿童在13岁时（2012年12月至2014年6月）重新参加了一项随访研究。此时，从279名儿童（134名干预组和145名对照组）采集的DNA进行了常见血清素转运体多态性的基因分型。220名儿童（110名干预组和110名对照组）既有基因数据又有依恋安全性数据，其中40%（44名干预组和45名对照组）携带血清素转运体基因的至少一个短等位基因。对于这220名个体，携带血清素转运体基因的至少一个短等位基因与相对于对照组依恋安全性高26%相关（OR = 3.86，p = 0.008，95%置信区间[1.42, 10.51]，d = 0.75），而仅携带长等位基因的干预组和对照组个体之间的安全性差异可忽略不计（1%）（OR = 0.95，p = 0.89，95%置信区间[0.45, 2.01]，d = 0.03）。以绝对风险表示，对于携带短等位基因的个体，干预组中观察到安全依恋的概率为84%（95%置信区间[73%，95%]），而对照组为58%（95%置信区间[43%，72%]）。对于携带两个长等位基因拷贝的个体，干预组中有70%（95%置信区间[59%，81%]）是安全的，而对照组中婴儿的这一比例为71%（95%置信区间[60%，82%]）。控制性别、母亲基因型和社会经济逆境指标（住房、就业、教育、电力、水）并没有改变这些结果。本研究的一个局限性是，我们仅能让随机分配到干预组和对照组的原始样本中的49%重新参加研究。因此，对于本亚样本中主要结果归因于干预的因果效应应谨慎对待。
当考虑婴儿血清素转运体多态性的基因型时，针对贫困孕妇的母婴依恋干预的效应大小在仅考虑短等位基因携带者时增加了2.5倍以上（从所有个体无论基因型的d = 0.29增加到d = 0.75），而在仅考虑携带两个长等位基因拷贝的个体时降低了10倍（从所有个体的d = 0.29降低到d = 0.03）。基因差异易感性意味着对所有参与者进行平均是一个误导性的疗效指标。该研究提出了关于政策制定者在实施心理社会干预时如何应对平衡公平（对所有人平等对待）和疗效（仅治疗那些基因使其可能受益的人）这一挑战的问题。
当前对照试验ISRCTN25664149。
