Semiparametric Regression with an Interval-Censored Covariate

In longitudinal studies, investigators are often interested in how the timing of an intermediateevent affects a future outcome. The intermediate event is often asymptomatic and its status can onlybe assessed at periodic examinations. Such an event is interval-censored in that its occurrence isonly known to lie in an interval induced by these examinations. The problem of interval-censoredcovariates has been previously studied only under restrictive conditions. In this dissertation, werelax these assumptions and present semiparametric regression models linking an interval-censoredintermediate event to various response variables.In the first chapter, we consider the case where the response variable of interest is continuous.We link the intermediate event and response through the rectified linear unit function, allowingfor interpretations in terms of duration of exposure to the intermediate event. We propose a nonparametricmaximum likelihood estimation approach using an expectation-maximization algorithm.We demonstrate the proposed approach through simulation studies and show that our method is robustto differential censoring patterns induced by missing visits. We present an application regressingsystolic blood pressure on interval-censored diabetes exposure.In the second chapter, we address the case where the response variable of interest is a rightcensoredevent time. We generalize the relationship between the outcome and intermediate event bylinking them through any non-constant function. We demonstrate the method through simulationstudies and a real data application.In the third chapter, we extend our previous work to longitudinal repeated measurements of acontinuous variable. We account for within-subject correlation through Gaussian-distributed randomeffects. We allow for time-dependent covariates to influence both the response and the occurrenceof the intermediate event. We demonstrate the approach through simulation studies and repeat theanalysis of Chapter 1 using repeated measurements of systolic blood pressure.In a brief fourth chapter, we develop regression models with an interval-censored covariate forresponse variables belonging to the exponential family. This extension provides researchers accessto analogs of generalized linear models such as logistic regression and the log-linear model. Wedemonstrate the performance of the approach, both with and without repeated measures, throughsimulation studies.Doctor of Philosoph

Semiparametric linear regression with an interval-censored covariate in the atherosclerosis risk in communities study

In longitudinal studies, investigators are often interested in understanding how the time since the occurrence of an intermediate event affects a future outcome. The intermediate event is often asymptomatic such that its occurrence is only known to lie in a time interval induced by periodic examinations. We propose a linear regression model that relates the time since the occurrence of the intermediate event to a continuous response at a future time point through a rectified linear unit activation function while formulating the distribution of the time to the occurrence of the intermediate event through the Cox proportional hazards model. We consider nonparametric maximum likelihood estimation with an arbitrary sequence of examination times for each subject. We present an EM algorithm that converges stably for arbitrary datasets. The resulting estimators of regression parameters are consistent, asymptotically normal, and asymptotically efficient. We assess the performance of the proposed methods through extensive simulation studies and provide an application to the Atherosclerosis Risk in Communities Study

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

IntroductionPirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment.MethodsHere we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs).ResultsOf 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy.ConclusionsPirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals

An investigation into the leadership behavior of high school athletic directors

There is no abstract available for this research paper.School of Physical EducationThesis (M.A.

An investigation into the leadership behavior of high school athletic directors

There is no abstract available for this research paper.Thesis (M.A.)School of Physical Educatio

Evaluation of bleeding risk in patients who received pirtobrutinib in the presence or absence of antithrombotic therapy

Abstract Clinical bleeding events are reported here from 773 patients with B‐cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT‐E], n  = 216; antithrombotic nonexposed [AT‐NE], n  = 557). Among the AT‐E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any‐grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3–51.5) in the AT‐E cohort and 181 patients (32.5%; 95% CI, 28.6–36.4) in the AT‐NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT‐E: 65.4%; AT‐NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT‐E: 22.7%; AT‐NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT‐E cohort and 11 patients (2.0%) in the AT‐NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT‐E and AT‐NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT‐E cohort, and one patient (0.2%) in the AT‐NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies