Causal Inference Methods for Assessing Neurodevelopment in Children Following Prenatal Exposure to Triptan Medications: A Dissertation

Background: Migraine headache is a chronic pain condition that affects 20% of women of reproductive age, and is often treated with triptans. Triptans are serotonin 1B, 1D, and 1F receptor agonists that act as vasoconstrictors and inhibitors of the trigeminal cervical complex as well as peripheral neurons; they cross the blood brain barrier and placenta, and as such are plausible neurodevelopmental teratogens. No studies have examined risk of neurodevelopmental problems in children with prenatal triptan exposure. This dissertation had three aims: (1) to examine risk of behavioral problems in children using in the presence of time-varying confounding by concomitant medication use; (2) to examine risk of temperamental, motor, and communication disturbances associated with prenatal triptans exposure, adjusting for unmeasured confounding by migraine type and severity; and (3) to examine changes in neurodevelopment over time associated with prenatal triptan exposure. Methods: This dissertation used data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort including more than 100,000 women recruited during their first prenatal ultrasound visit. Aims 1 and 3 used marginal structural models to assess the risk of (1) neurodevelopmental problems at age 36 months (Aim 1), or (2) change in risk of neurodevelopmental problems from 18 to 36 months (Aim 3) associated with prenatal triptan exposure. Aim 2 used propensity matching and calibration to adjust for unmeasured confounding by migraine type, severity, and attitudes towards medication use in pregnancy. Neurodevelopmental outcome measures included the Child Behavior Checklist (CBCL), the Emotionality, Activity, and Temperament Scale (EAS), and the Ages and Stages Questionnaire (ASQ). Exposure to triptans was ascertained by self-report. Results: Prenatal triptan exposure was associated with greater externalizing behavior problems at 18 and 36 months, as well as greater increases in emotionality and activity from 18 to 36 months. We observed no association between triptan exposure and motor skills or communication problems; triptan use during pregnancy was associated with migraine severity but not migraine type, and adjustment for unmeasured migraine characteristics moved effect estimates towards the null. Conclusions: Prenatal triptan exposure is associated with externalizing-type behaviors and temperament in children, while migraine itself is associated with internalizing-type behaviors and temperament. The use of concomitant medications and the severity of the underlying condition both exerted substantial influence on observed effect estimates, and should be considered in any future studies of triptan medication use in pregnancy

AN EXPLORATION INTO THE REPRESENTATION OF FEMALE DEATH IN CONTEMPORARY PERFORMANCE OF SHAKESPEAREAN TRAGEDY

This thesis will explore the representation of female death in contemporary performance of Shakespearean tragedy, with particular attention paid to Blanche McIntyre’s directorial decisions in Titus Andronicus for the Royal Shakespeare Company (RSC) in 2017. I will assess the symbolic, tropic representation of femininity through history, the aesthetic encoding of the female form in death, and psycho-sociological theories which determine humanity as indebted to this image. By noting the ways in which McIntyre represents Lavinia as the object of desire and site of tragedy, I will be at liberty to assess the patriarchal structure of narrative inherent in Shakespeare’s tragedies, as well as the progression of tropes which incline directors toward the beautiful aesthetics of tragic females’ deaths. Noting the ways in which Shakespeare’s plays were originally performed, I will be able to see the tendencies of contemporary performance toward heightening the aesthetic encoding of the female corpse

Treatments for pregestational chronic conditions during pregnancy: emulating a target trial with a treatment decision design

As a solution to methodologic challenges inherent to estimating causal effects of exposures in early pregnancy, we suggest emulating a target trial using a treatment decision design, wherein time zero is centered around clinical landmarks where treatment decisions may occur, such as the date of preconception counseling or prenatal care initiation. These ideas are illustrated via protocols for two target trials in large administrative databases, antidepressant use for pre-existing depressive disorder and antihypertensive medication use for mild-to-moderate chronic hypertension. Careful consideration of these issues is critical to the identification of the causal effects of early-pregnancy pharmacotherapies on pregnancy outcomes

Longitudinal changes in neurodevelopmental outcomes between 18 and 36 months in children with prenatal triptan exposure: findings from the Norwegian Mother and Child Cohort Study

OBJECTIVE: This study sought to determine whether changes in neurodevelopmental outcomes between 18 and 36 months of age were associated with prenatal exposure to triptan medications, a class of 5-HT receptor agonists used in the treatment of migraine. METHOD: Using data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort that includes nearly 40% of all pregnancies in Norway from 1999 to 2008, we identified 50 469 mother-child dyads who met inclusion criteria and were present for at least one follow-up assessment at 18 or 36 months postpartum. Neurodevelopment was assessed using the Child Behaviour Checklist, the Emotionality, Activity, and Shyness Questionnaire, and the Ages and Stages Questionnaire. We used generalised estimating equations to evaluate change from 18 to 36 months for children prenatally exposed to triptans, relative to contrast groups, and used marginal structural models with inverse probability of treatment and censoring weights to address time-varying exposure and confounding as well as loss to follow-up. RESULTS: Among eligible participants (n=50 469), 1.0% used a triptan during pregnancy, 2.0% used triptans prior to pregnancy only, 8.0% reported migraine without triptan use and 89.0% had no history of migraine. Children with prenatal triptan exposure had greater increases in emotionality (r-RR 2.18, 95% CI 1.03 to 4.53) and activity problems (r-RR 1.70, 95% CI 1.02 to 2.8) compared to children born to mothers who discontinued triptan use prior to pregnancy. CONCLUSION: Prenatal triptan exposure was associated with changes over time in externalising-type behaviours such as emotionality and activity, but not with internalising-type behaviours

Improving generalization of machine learning-identified biomarkers with causal modeling: an investigation into immune receptor diagnostics

Machine learning is increasingly used to discover diagnostic and prognostic biomarkers from high-dimensional molecular data. However, a variety of factors related to experimental design may affect the ability to learn generalizable and clinically applicable diagnostics. Here, we argue that a causal perspective improves the identification of these challenges, and formalizes their relation to the robustness and generalization of machine learning-based diagnostics. To make for a concrete discussion, we focus on a specific, recently established high-dimensional biomarker - adaptive immune receptor repertoires (AIRRs). We discuss how the main biological and experimental factors of the AIRR domain may influence the learned biomarkers and provide easily adjustable simulations of such effects. In conclusion, we find that causal modeling improves machine learning-based biomarker robustness by identifying stable relations between variables and by guiding the adjustment of the relations and variables that vary between populations

The influence of iron status and genetic polymorphisms in the HFE gene on the risk for postoperative complications after bariatric surgery: a prospective cohort study in 1,064 patients

<p>Abstract</p> <p>Background</p> <p>Gastric bypass surgery is a highly effective therapy for long-term weight loss in severely obese patients, but carries significant perioperative risks including infection, wound dehiscence, and leaks from staple breakdown. Iron status can affect immune function and wound healing, thus may influence peri-operative complications. Common mutations in the HFE gene, the gene responsible for the iron overload disorder hereditary hemochromatosis, may impact iron status.</p> <p>Methods</p> <p>We analyzed 1064 extremely obese Caucasian individuals who underwent open and laparoscopic Roux-n-Y gastric bypass surgery at the Geisinger Clinic. Serum iron, ferritin, transferrin, and iron binding capacity were measured pre-operatively. All patients had intra-operative liver biopsies and were genotyped for the C282Y and H63D mutations in the HFE gene. Associations between surgical complications and serum iron measures, HFE gene status, and liver iron histology were determined.</p> <p>Results</p> <p>We found that increased serum iron and transferrin saturation were present in patients with any post-operative complication, and that increased serum ferritin was also increased in patients with major complications. Increased serum transferrin saturation was also associated with wound complications in open RYGB, and transferrin saturation and ferritin with prolonged lengths of stay. The presence of 2 or more HFE mutations was associated with overall complications as well as wound complications in open RYGB. No differences were found in complication rates between those with stainable liver iron and those without.</p> <p>Conclusion</p> <p>Serum iron status and HFE genotype may be associated with complications following RYGB surgery in the extremely obese.</p

The ChatGPT Artificial Intelligence Chatbot: How Well Does It Answer Accounting Assessment Questions?

ChatGPT, a language-learning model chatbot, has garnered considerable attention for its ability to respond to users’ questions. Using data from 14 countries and 186 institutions, we compare ChatGPT and student performance for 28,085 questions from accounting assessments and textbook test banks. As of January 2023, ChatGPT provides correct answers for 56.5 percent of questions and partially correct answers for an additional 9.4 percent of questions. When considering point values for questions, students significantly outperform ChatGPT with a 76.7 percent average on assessments compared to 47.5 percent for ChatGPT if no partial credit is awarded and 56.5 percent if partial credit is awarded. Still, ChatGPT performs better than the student average for 15.8 percent of assessments when we include partial credit. We provide evidence of how ChatGPT performs on different question types, accounting topics, class levels, open/closed assessments, and test bank questions. We also discuss implications for accounting education and research

Sharing vocabularies: towards horizontal alignment of values-driven business functions

This paper highlights the emergence of different ‘vocabularies’ that describe various values-driven business functions within large organisations and argues for improved horizontal alignment between them. We investigate two established functions that have long-standing organisational histories: Ethics and Compliance (E&C) and Corporate Social Responsibility (CSR). By drawing upon research on organisational alignment, we explain both the need for and the potential benefit of greater alignment between these values-driven functions. We then examine the structural and socio-cultural dimensions of organisational systems through which E&C and CSR horizontal alignment can be coordinated to improve synergies, address tensions, and generate insight to inform future research and practice in the field of Business and Society. The paper concludes with research questions that can inform future scholarly research and a practical model to guide organizations’ efforts towards inter-functional, horizontal alignment of values-driven organizational practice