Methodological Considerations and Limitations

The socio-economic context of the cookie delay task. The cookie delay task, which was used in this dissertation as a performance-based measure of inhibition, mimics the marshmallow task. The value of the marshmallow task in predicting long-term outcomes like academic achievement has been called into question. A recent study found that much of the variability in the delayed gratification task can be accounted for by family background factors such as socioeconomic status.237 _{When we additionally adjusted for maternal education (as a} proxy for socioeconomic status) in tests of association between maternal thyroid function and cookie delay task performance, results did not change. That being said, the socioeconomic background of women included in this study was relatively homogeneous.

Limitations of the weighting scheme. Because the second paper of this dissertation investigated continuous executive function outcomes, which are related to ADHD, the

distribution of outcome scores theoretically are biased by the intentional oversampling of preschool children with symptoms indicative of ADHD. To address the potential bias imposed by this selection scheme, I weighted regression models by the inverse probability of preschool ADHD status. The purpose of these weights was to re-distribute the relative proportion of preschool ADHD cases and controls in the N=342 clinical sample to match the relative

proportion of those who screened positive and negative for ADHD in the 3-year questionnaire among those eligible for the ADHD sub-study (include numbers here). The prevalence of those screening positive for ADHD symptoms was 12.6% in the eligible population, which is

comparable with the estimated prevalence of preschool ADHD (10%).221

This weighting scheme has some limitations. First, it implicitly assumes that screening positive for ADHD is equivalent to testing positive for ADHD. We are weighting by clinically- evaluated ADHD status; however, selection into the sub-study was actually based on scores on a parent-completed screening inventory. That being said, Overgaard and colleagues, who also used the ADHD sub-study, argued that: “Our sample may resemble a primary health care unit, where concerned parents ask whether their active preschool child might have ADHD.”217 _Thus, the sampling structure of the ADHD sub-study can be said to have some ecological validity. A second limitation is that the weights do not reflect the fact that exclusion from these analyses differed based on screening status and test results. Specifically, among those who screened negative, those who tested negative for ADHD were included, whereas among those who screened positive, those who tested negative for ADHD were excluded.

One-time measure of maternal thyroid function. Maternal thyroid function was measured only once: at 17 weeks’ gestation. Because maternal thyroid hormone levels change during pregnancy, this may be considered a limitation of this dissertation. However, of all the potential measurement time points, this particular timing of measurement may be

advantageous for several reasons. First, 17 weeks falls within the first half of gestation, during which the fetus continues to rely on the maternal thyroid hormone supply to support

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neurodevelopment.83,84 _{Second, a recent systematic review of animal and human studies of the} association between maternal thyroid function and fetal neurodevelopment indicate that maternal thyroid function earlier in gestation has a greater impact on neurodevelopment than later.68 _{However, maternal thyroid hormones change the most during the first trimester, and} begin to level off thereafter.69 _{Thus, it would be valuable to additionally measure thyroid} function in the first trimester.

Limitations in the directed acyclic graph (DAG). A challenge in creating the DAG underlying this dissertation project is that the biological mechanisms linking many of the

relevant variables are not well characterized. One example of this limitation is the biological role of maternal pre-pregnancy BMI. There is some evidence that BMI causally influences thyroid hormone levels,238 _{though the mechanism is unclear and the effect may be restricted to clinical} thyroid hormone disorders and/or BMI levels outside of the healthy range.171,172 _{Similarly, there} is some evidence that maternal BMI influences offspring ADHD and cognitive

development;173,174,239 _{however, it is possible that this effect is due to unmeasured confounding} by familial factors.240 _{In this dissertation, I addressed these limitations by conducting sensitivity} analyses investigating the effect of additionally adjusting for BMI. Results did not change when maternal pre-pregnancy BMI was added to the model. That being said, the results of this single investigation cannot speak to the underlying biological mechanisms linking BMI, maternal thyroid function, and child neurodevelopment: these mechanisms remain to be illuminated.

Missing performance-based executive function data. Children were only 3.5

years of age when they took part in the performance-based measures of executive function (including the working memory subscales of the SB5 battery, the NEPSY statue task, and the cookie delay task). Remaining on task, across multiple tasks, could be difficult for children of this age due to factors related to executive function (e.g. attention, inhibition) as well as factors that are not directly related to executive function (e.g. fatigue or energy level, hunger). Potential non-random missingness is thus a concern. More than 20% of the observations were missing for

the SB5 verbal working memory (and consequently the working memory index), and more than 10% of observations were missing for the NEPSY statue task. Our sensitivity analysis suggested that, in extreme scenarios where the unobserved outcome values were differential with respect to the exposure, the bounds on the estimated main effects on the SB5 verbal working memory (and working memory index) and the NEPSY statue task are relatively broad. That being said, we did not observe clear patterns of main effects; thus, our interpretations remain unchanged by these sensitivity analyses. These sensitivity analyses do, however, highlight the importance of considering how children’s ability to complete performance-based measures of executive function could potentially affect estimated associations.