ABSTRACT Hypothyroidism is a common endocrine disorder affecting nearly 10% of the US population. The first line treatment of hypothyroidism is levothyroxine (L T4), a synthetic form of thyroid hormone. The primary goals of treatment are to resolve hypothyroid symptoms and restore normal biochemical thyroid function. Managing hypothyroidism is challenging because it often requires multiple L T4 dose adjustments over a patient's lifetime. Cross-sectional studies of hypothyroidism management have demonstrated that at least one-third of patients are over- or undertreated, which both lead to serious adverse health outcomes. Several outcome studies have suggested that adverse cardiovascular events are more likely to occur the longer overtreatment or undertreatment persist. While these studies have reinforced the importance of durable maintenance of normal thyroid function levels, there are no established methods for clinicians or their patients to measure the degree to which thyroid function is controlled over the treatment course. An intuitive measure of thyroid function control is the serum value of thyroid stimulating hormone (TSH). However, TSH is a cross-sectional marker of thyroid function and does not account for changes in thyroid function over time. Longitudinal TSH trajectory represents a candidate outcome measure of thyroid function control during hypothyroidism treatment. TSH trajectories have been previously studied to identify different classes of thyroid function patterns during pregnancy, but not during thyroid hormone treatment. In addition, the time-in-range (TIR) treatment parameter is a potential marker of thyroid function control over time. As an example, glycemic TIR, a reported output of continuous glucose monitoring, measures the duration of time spent within specific glycemic ranges and has emerged as a validated predictor of diabetes complications. Adapting a method used to estimate therapeutic TIR from repeated measures of clotting parameters (i.e., INR) could allow for the estimation of TIR of L T4 treatment from repeated TSH values. The primary goal of this NIDDK Diabetes Research & Training Center (DRTC) Pilot & Feasibility application is to provide evidence for longitudinal outcome measures of thyroid function control in the management of hypothyroidism. Using a large longitudinal database of L T4-treated patients in the University of Chicago Medicine health system over 1 0 years (2010 - 2019), the Pl (Dr. Matthew Ettleson) will complete the following specific aims: 1) determine the relationship between TSH trajectory class and cardiovascular outcomes (incidence of atrial fibrillation, heart failure, stroke, and myocardial infarction), and 2) determine the association between a TSH-based therapeutic time-in-range treatment parameter and cardiovascular outcomes. The findings of this study will serve as preliminary data for a future research grant application investigating multiple approaches to improve hypothyroidism mana...