NONLINEAR MODELS IN MULTIVARIATE POPULATION BIOEQUIVALENCE TESTING

In this dissertation a methodology is proposed for simultaneously evaluating the population bioequivalence (PBE) of a generic drug to a pre-licensed drug, or the bioequivalence of two formulations of a drug using multiple correlated pharmacokinetic metrics. The univariate criterion that is accepted by the food and drug administration (FDA) for testing population bioequivalence is generalized. Very few approaches for testing multivariate extensions of PBE have appeared in the literature. One method uses the trace of the covariance matrix as a measure of total variability, and another uses a pooled variance instead of the reference variance. The former ignores the correlation between the measurements while the later is not equivalent to the criterion proposed by the FDA in the univariate case, unless the variances of the test and reference are identical, which reduces the PBE to the average bioequivalence. The confidence interval approach is used to test the multivariate population bioequivalence by using a parametric bootstrap method to evaluate the 100% (1-alpha) confidence interval. The performance of the multivariate criterion is evaluated by a simulation study. The size and power of testing for bioequivalence using this multivariate criterion are evaluated in a simulation study by altering the mean differences, the variances, correlations between pharmacokinetic variables and sample size. A comparison between the two published approaches and the proposed criterion is demonstrated. Using nonlinear models and nonlinear mixed effects models, the multivariate population bioequivalence is examined. Finally, the proposed methods are illustrated by simultaneously testing the population bioequivalence for AUC and Cmax in two datasets

Polypectomy Techniques, Endoscopist Characteristics, and Serious Gastrointestinal Adverse Events

Background: A use of polypectomy techniques by endoscopist specialty (primary care, surgery, and gastroenterology) and experience (volume), and associations with serious gastrointestinal adverse events, were examined. Methods: A retrospective follow-up study with ambulatory surgery and hospital discharge datasets from Florida, 1999-2001, was used. Thirty-day hospitalizations due to colonic perforations and gastrointestinal bleeding were investigated for 323,585 patients. Results: Primary care endoscopists and surgeons used hot biopsy forceps/ablation, while gastroenterologists provided snare polypectomy or complex colonoscopy. Low-volume endoscopists were more likely to use simpler rather than complex procedures. For hot forceps/ablation and snare polypectomy, low- and medium-volume endoscopists reported higher odds of adverse events. For complex colonoscopy, higher odds of adverse events were reported for primary care endoscopists (1.74 [95%CI, 1.18 to 2.56]) relative to gastroenterologists Conclusions: Endoscopists regardless of specialty and experience can safely use cold biopsy forceps. For hot biopsy and snare polypectomy, low volume, but not specialty, contributed to increased odds of adverse events. For complex colonoscopy, primary care specialty, but not low volume, added to the odds of adverse events. Comparable outcomes were reported for surgeons and gastroenterologists. Cross-training and continuing medical education of primary care endoscopists in high-volume endoscopy settings are recommended for complex colonoscopy procedures

Suboptimal geographic accessibility to comprehensive HIV care in the US: regional and urban–rural differences

Achieving US state and municipal benchmarks to end the HIV epidemic and promote health equity requires access to comprehensive HIV care. However, this care may not be geographically accessible for all people living with HIV (PLHIV). We estimated county-level drive time and suboptimal geographic accessibility to HIV care across the contiguous US, assessing regional and urban–rural differences. We integrated publicly available data from four federal databases to identify and geocode sites providing comprehensive HIV care in 2015, defined as the co-located provision of core HIV medical care and support services. Leveraging street network, US Census and HIV surveillance data (2014), we used geographic analysis to estimate the fastest one-way drive time between the population-weighted county centroid and the nearest site providing HIV care for counties reporting at least five diagnosed HIV cases. We summarized HIV care sites, county-level drive time, population-weighted drive time and suboptimal geographic accessibility to HIV care, by US region and county rurality (2013). Geographic accessibility to HIV care was suboptimal if drive time was \u3e30 min, a common threshold for primary care accessibility in the general US population. Tests of statistical significance were not performed, since the analysis is population-based. We identified 671 HIV care sites across the US, with 95% in urban counties. Nationwide, the median county-level drive time to HIV care is 69 min (interquartile range (IQR) 66 min). The median county-level drive time to HIV care for rural counties (90 min, IQR 61) is over twice that of urban counties (40 min, IQR 48), with the greatest urban–rural differences in the West. Nationally, population-weighted drive time, an approximation of individual-level drive time, is over five times longer in rural counties than in urban counties. Geographic access to HIV care is suboptimal for over 170,000 people diagnosed with HIV (19%), with over half of these individuals from the South and disproportionately the rural South. Nationally, approximately 80,000 (9%) drive over an hour to receive HIV care. Suboptimal geographic accessibility to HIV care is an important structural barrier in the US, particularly for rural residents living with HIV in the South and West. Targeted policies and interventions to address this challenge should become a priority

Pain site frequency and location in sickle cell disease: The PiSCES project

Treatment options for sickle cell disease (SCD) pain could be tailored to pain locations. But few epidemiologic descriptions of SCD pain location exist; these are based on few subjects over short time periods. We examined whether SCD pain locations vary by disease genotype, gender, age, frequency of pain, depression, pain crisis or healthcare utilization

Evaluating Bilateral Phenomena: The Case of Pain in Sickle Cell Disease

Symmetry in biological systems is the occurrence of an event on both sides of the system. The term bilateralism was introduced to represent this phenomenon, and it was defined as the conditional co-occurrence of two events given that at least at one of them has occurred. This phenomenon is highly associated with the prevalence of each of the events. Two parameters were developed to evaluate the presence of this phenomenon, testing whether events co-occur with higher probability than would be expected by chance. Nonparametric confidence intervals were constructed using the bootstrap percentile method. These non parametric confidence intervals were used in testing the null hypothesis of no bilateralism.A simulation study was performed to examine the properties of the two bilateralism parameters\u27 estimates. The size and power of the tests of bilateralism were examined under a variety of sample sizes and prevalences of the two events. The simulation study showed that both parameter estimates have similar properties, and the tests have similar size and power. The power of the test was affected by the prevalence of either event, the differences in the prevalences, the sample size and by number of events that occur simultaneously. The methodology of testing for bilateralism was applied on data from the Pain in Sickle Cell Epidemiology Study (PiSCES). This study collected up to 6 months worth of daily diaries about pain and medical utilization from patients with sickle cell disease. Each diary recorded the body site and side where pain was experienced over the past 24 hours. The sample consists of 119 subjects who completed at least 50 daily pain diaries (reference). Information about the subjects age, gender and sickle cell genotype were also available. Nine body sites (5 upper peripheral, and 4 lower peripheral site) were analyzed to test for bilateralism. Bilateralism was tested for each subject and each site separately. The associations of prevalence of bilateralism on each site, and percentages of sites that hurt bilaterally with age, gender and genotype where studied.The results show a high prevalence of bilateral pain among sickle cell patients at all sites. Age gender and genotype were associated with higher prevalence in bilateral pain in some, but not all sites. The percentage of sites that have bilateral pain is also associated with the number of sites that have pain

Letter to the Editor: Direct inguinal hernia containing a prolapsed bladder in an infant

No Abstract

Development of New Mental and Physical Health Sequelae among US Veterans after COVID-19

Background:COVID-19 sequelae among veterans need evaluation. Design: Propensity-score-matched retrospective cohort study. Participants: A total 778,738 veterans, who were tested for COVID-19 at VA facilities between 20 February 2020–27 March 2021. Main Outcomes: Development of new physical and mental health conditions (incidence) during the follow-up period of 7 days to 3 months after the diagnosis of COVID-19. Results: Out of 778,738 veterans, 149,205 (19.2%) were inpatients and 629,533 (80.8%) were outpatients. 123,757 (15.9%) diagnosed with COVID-19. Mean age was 61 ± 15.4, mostly men (89%) who were White (68%) and non-Hispanic (88%). In hospitalized patients, COVID-19 is associated with significantly higher incidences of physical conditions (venous thromboembolism (5.8% vs. 2.9%, p < 0.001), pulmonary circulation disorder (5.1% vs. 2.9%, p < 0.001), chronic lung disease (8.4% vs. 4.3%, p < 0.001), acute kidney injury (16.4% vs. 9.3%, p < 0.001), chronic kidney disease (6.5% vs. 4.8%, p < 0.001), cardiac arrhythmia (15.2% vs. 10.9%, p < 0.001), complicated hypertension (12% vs. 8.5%, p < 0.001), coagulopathy (6.1% vs. 2.6%, p < 0.001), fluid/electrolyte disorders (24.4% vs. 12.6%, p < 0.001) and neurological disorders (7.1% vs. 3.8%, p < 0.001)) and mental health conditions (depressive episode (6.6% vs. 4.3%, p < 0.001), adjustment disorder (2.5% vs. 1.7%, p < 0.001), insomnia (4.9% vs. 3.2%, p < 0.001) and dementia (3.0% vs. 1.9%, p < 0.001)) compared to propensity-matched hospitalized COVID-19 negative patients. In outpatient settings, COVID-19 diagnosis is associated with smaller increase in the incidences of the physical sequelae. Conclusions: In this propensity-score-matched analysis of US veterans, COVID-19 survivors, especially those who were hospitalized, developed new physical and mental health sequelae at a significantly higher rate than those without COVID-19

Work Continuation while Treated for Breast Cancer

Given the short- and long-term disabilities associated with breast cancer and its treatment, the authors investigate the influence of workplace accommodations on the employment and hours worked of women newly diagnosed with breast cancer. Accommodations that allow women to work fewer hours or that ease the burden of work could also generate health benefits by reducing workplace demands and allowing women more time to tend to treatment needs and recovery. In prior research, the authors found modest labor supply impacts on employment for this group of women. Evidence from this study suggests that some accommodations are associated with fewer hours worked, while some are associated with higher employment or hours. In addition, some of the accommodations that may affect hours of work-sometimes positively and sometimes negatively-are associated with positive health benefits