A PARTIAL LIKELIHOOD APPROACH TO LONGITUDINAL CATEGORICAL DATA USING A CONTINUOUS TIME SEMI-MARKOV CHAIN MODEL

Longitudinal studies have been critical in understanding the characteristics of chronic diseases or interventions. Since many processes have natural multi-categorical responses over time, multi-state stochastic models have been used to estimate the transition rates between stages. Some multi-state models applied in practice assume the Markov property. The Markov property constrains the sojourn distribution to be exponentially distributed. While useful theoretical properties arise by the Markov assumption, we will consider a more flexible framework by allowing arbitrarily distributed waiting times. This describes a semi-Markov process which has already been applied to various fields in Public Health. Similar to Markov model developments, semi-Markov models have been extended to add covariate e↵ects on each transition intensity for better estimation. Statistical inference methods for semi-Markov chains are still being developed for unique problems for ecient estimation and computational feasibility. Particularly, in this dissertation, we have developed a partial likelihood based approach under a semi-Markov framework. First, we will consider estimating parameters for a three to four stage process by a partial likelihood approach and examining the sensitives of the transition intensity estimates with models that have a gamma or Weibull sojourn time. This approach will estimate the hazard rates between discrete stages. Secondly, we will extend the semiMarkov model to include covariate e↵ects on the transition rates and again, analyze its results with models assuming the gamma or Weibull sojourn time. Two applications will be considered to illustrate our method: A caregiver stress-level study from the Baylor’s Alzhemier’s Disease and Memory Disorders Center and a depression severity level study from the Hispanic Established Population for the Epidemiological Study of the Elderly (HEPESE)

Ground plane fin-shaped field effect transistor (GP-FinFET): A FinFET for low leakage power circuits

In this paper, a fin-shaped field effect transistor (FinFET) structure which uses ground plane concept is proposed and theoretically investigated. The ground plane reduces the coupling of electric field between the source and drain reducing drain-induced barrier lowering (DIBL). To assess the performance of the proposed structure, some device characteristics of the structure have been compared with those of silicon on insulator-FinFET (SOI-FinFET) and Bulk-FinFET structures (where the BOX layer covers all the regions except the channel region). In addition, we compare different characteristics of static random access memory (SRAM) cells based on the proposed device structure as well as SOI-FinFET and Bulk-FinFET structures. The characteristics include standby power consumption, and read static noise margin (SNM). Finally, the behavior of the proposed device in the presence of dimensional variations (channel length and thin film thickness variations) and random dopant fluctuation (RDF) are studied and compared with those of the other two structures. (C) 2012 Elsevier B.V. All rights reserved

Effect of proprotein convertase subtilisin/kexin type 9 inhibition on cancer events: A pooled, post hoc, competing risk analysis of alirocumab clinical trials

Abstract Objective Assess the risk of new and worsening cancer events among participants who received the lipid‐lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. Design Pooled post hoc analysis. Setting Six phase 3 or phase 4 placebo‐controlled randomised trials with alirocumab. Participants A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). Intervention Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low‐density lipoprotein cholesterol <50 mg/dL not achieved, or placebo, all every 2 weeks. All participants received background high‐intensity or maximum‐tolerated statin therapy. Outcomes and Measures The first new or worsening incident cancer events were assessed during the treatment‐emergent adverse event period. Four outcomes were evaluated: any‐neoplasm, malignant neoplasms, broad definition of hormone‐sensitive cancers, and stricter definition of hormone‐sensitive cancers. Sub‐distribution hazard ratios and 95% confidence intervals (CIs) were estimated using a competing risk framework, with death as a competing risk. Results Considering both treatment arms in aggregate, 969 (4.03%), 779 (3.24%), 178 (0.74%) and 167 (0.69%) patients developed any neoplasm, malignant neoplasms, broad definition of hormone‐sensitive cancer and strict definition of hormone‐sensitive cancer events, respectively. There was no significant difference in the risk of having any neoplasm in the alirocumab versus the placebo group (sub‐distribution hazards ratio [95% CI], 0.93 [0.82–1.1]; p = 0.28). A nominally lower risk of having any neoplasms with alirocumab was observed among subjects aged ≥64 years (sub‐distribution hazards ratio 0.83; 95% CI, 0.70–0.99). Conclusions Intensive low‐density lipoprotein cholesterol lowering with a proprotein convertase subtilisin/kexin type 9 inhibitor combined with statin does not appear to increase the risk of new or worsening cancer events

Casirivimab + imdevimab accelerates symptom resolution linked to improved COVID-19 outcomes across susceptible antibody and risk profiles

Abstract Severe, protracted symptoms are associated with poor outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a placebo-controlled study of casirivimab and imdevimab (CAS + IMD) in persons at high risk of severe coronavirus disease 2019 (COVID-19; n = 3816), evolution of individual symptoms was assessed for resolution patterns across risk factors, and baseline SARS-CoV-2-specific antibody responses against S1 and N domains. CAS + IMD versus placebo provided statistically significant resolution for 17/23 symptoms, with greater response linked to absence of endogenous anti–SARS-CoV-2 immunoglobulin (Ig)G, IgA, or specific neutralizing antibodies at baseline, or high baseline viral load. Resolution of five key symptoms (onset days 3–5)—dyspnea, cough, feeling feverish, fatigue, and loss of appetite—independently correlated with reduced hospitalization and death (hazard ratio range: 0.31–0.56; P < 0.001–0.043), and was more rapid in CAS + IMD-treated patients lacking robust early antibody responses. Those who seroconverted late still benefited from treatment. Thus, highly neutralizing COVID-19-specific antibodies provided by CAS + IMD treatment accelerated key symptom resolution associated with hospitalization and death in those at high risk for severe disease as well as in those lacking early, endogenous neutralizing antibody responses

REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters.

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail