Background

Findings from epidemiological studies of prenatal phthalate exposure and child cognitive development are inconsistent. Methods for evaluating mixtures of phthalates, such as weighted quantile sum (WQS) regression, have rarely been applied. We developed a new extension of the WQS method to improve specificity of full-sample analyses and applied it to estimate associations between prenatal phthalate mixtures and cognitive and language outcomes in a diverse pregnancy cohort.

Methods

We measured 22 phthalate metabolites in third trimester urine from mother-child dyads who completed early childhood visits in the Conditions Affecting Neurodevelopment and Learning in Early childhood (CANDLE) study. Language and cognitive ability were assessed using the Bayley Scales of Infant Development (age 3) and the Stanford Binet-5 (age 4–6), respectively. We used multivariable WQS regression to identify phthalate mixtures that were negatively and positively associated with language score and full-scale IQ, in separate models, adjusted for maternal IQ, race, marital status, smoking, BMI, socioeconomic status (SES), child age, sex, and breastfeeding. We evaluated effect modification by sex and SES. If full sample 95% WQS confidence intervals (which are known to be anti-conservative) excluded the null, we calculated a p-value using a permutation test (p_permutation). The performance of this new approach to WQS regression was evaluated in simulated data. We compared the power and type I error rate of WQS regression conducted within datasets split into training and validation samples (WQS_Split) and in the full sample (WQS_Nosplit) to WQS regression with a permutation test (WQS_permutation). Individual metabolite associations were explored in secondary analyses.

Results

The analytic sample (N = 1015) was 62.1% Black/31.5% White, and the majority of mothers had a high school education or less (56.7%) at enrollment. Associations between phthalate mixtures and primary outcomes (language score and full-scale IQ) in the full sample were null. Individual metabolites were not associated with IQ, and only one metabolite (mono-benzyl phthalate, MBzP) was associated with Bayley language score (β = −0.68, 95% CI: −1.37, 0.00). In analyses stratified by sex or SES, mixtures were positively and negatively associated with outcomes, but the precision of full-sample WQS regression results were not supported by permutation tests, with one exception. In the lowest SES category, a phthalate mixture dominated by mono-methyl phthalate (MMP) and mono-carboxy-isooctyl phthalate (MCOP) was associated with higher language scores (β_{low SES} = 2.41, full-sample 95%CI: 0.58, 4.24; p_permutation = 0.04). Performance testing in simulated data showed that WQS_permutation had improved power over WQS_Split (90% versus 56%) and a lower type I error rate than WQS_Nosplit (7% versus 47%).

Conclusions

In the largest study of these relationships to date, we observed predominantly null associations between mixtures of prenatal phthalates and both language and IQ. Our novel extension of WQS regression improved sensitivity to detect true associations by obviating the need to split the data into training and test sets and should be considered for future analyses of exposure mixtures.

中文翻译：

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影响幼儿期神经认知发展和学习的条件 (CANDLE) 研究中接触产前邻苯二甲酸酯混合物和神经发育

背景

关于产前邻苯二甲酸盐接触和儿童认知发展的流行病学研究结果并不一致。评估邻苯二甲酸盐混合物的方法，例如加权分位数和（WQS）回归，很少被应用。我们开发了 WQS 方法的新扩展，以提高全样本分析的特异性，并将其应用于估计不同妊娠队列中产前邻苯二甲酸盐混合物与认知和语言结果之间的关联。

方法

我们测量了在影响幼儿期神经发育和学习的条件 (CANDLE) 研究中完成幼儿期访视的母子二人妊娠晚期尿液中的 22 种邻苯二甲酸酯代谢物。分别使用贝利婴儿发育量表（3 岁）和斯坦福 Binet-5（4-6 岁）评估语言和认知能力。我们使用多变量 WQS 回归来识别与语言分数和全面智商呈负相关和正相关的邻苯二甲酸盐混合物，在单独的模型中，根据母亲的智商、种族、婚姻状况、吸烟、体重指数、社会经济地位 (SES)、儿童年龄进行调整、性和母乳喂养。我们评估了性别和社会经济地位对影响的影响。_{如果全样本 95% WQS 置信区间（已知是反保守的）排除了空值，我们使用排列检验 (p permutation} ) 计算 p 值。这种 WQS 回归新方法的性能在模拟数据中进行了评估。我们将在分为训练和验证样本 (WQS _Split ) 和完整样本 (WQS _Nosplit ) 的数据集中进行的 WQS 回归的功效和 I 类错误率与带有排列测试 (WQS _permutation ) 的 WQS 回归进行比较。在二次分析中探讨了个体代谢物的关联。

结果

分析样本 (N = 1015) 为 62.1% 黑人/31.5% 白人，大多数母亲在入学时受过高中或以下教育 (56.7%)。在整个样本中，邻苯二甲酸盐混合物与主要结果（语言分数和全面智商）之间的关联为零。个别代谢物与智商无关，只有一种代谢物（邻苯二甲酸单苄酯，MBzP）与贝利语言评分相关（β = -0.68，95% CI：-1.37，0.00）。在按性别或社会经济地位分层的分析中，混合与结果呈正相关和负相关，但全样本 WQS 回归结果的精度不受排列检验的支持，只有一个例外。在最低 SES 类别中，以邻苯二甲酸单甲酯 (MMP) 和邻苯二甲酸单羧基异辛酯 (MCOP) 为主的邻苯二甲酸酯混合物与较高的​​语言分数相关（β 低 SES = 2.41，全样本 95 _%  CI：0.58， 4.24；p_排列 = 0.04）。模拟数据中的性能测试表明，WQS_{排列比 WQS Split}具有更高的功效（90% 对 56%），并且比 WQS _Nosplit具有更低的 I 类错误率（7% 对 47%）。

结论

在迄今为止对这些关系进行的最大规模的研究中，我们观察到产前邻苯二甲酸盐混合物与语言和智商之间主要没有关联。我们对 WQS 回归的新颖扩展通过消除将数据分为训练集和测试集的需要，提高了检测真实关联的灵敏度，并且应该考虑用于未来的暴露混合物分析。