Survival models for censored point processes

In studies of recurrent events, there can be a lot of information about a cohort over a period of time, but it may not be possible to extract as much information from the data as would be liked. This thesis considers data on individuals experiencing recurrent events, before and after they are randomised to treatment. The prerandomisation outcome is a period count, while the post-randomisation outcome is a survival time. Standard survival analysis may treat the pre-randomisation period count as a covariate, but it is proposed that point process models will give a more precise estimate of the treatment effect. A joint model is presented, based on a Poisson process with individual frailty. The pre-randomisation seizure counts are distributed as Poisson variables with rate depending on explanatory variables as well as a random frailty. The model for the post-randomisation survival times is the exponential distribution with the same individual seizure rate, modified by a multiplicative treatment effect. A conjugate mixing distribution (frailty) is used, and alternative mixing distributions are also discussed. The model is motivated by and illustrated on individual patient data from five randomised trials of two treatments for epilepsy. The data are presented, and the standard analyses are contrasted with the results of the joint model. This thesis also considers the relative efficiency of the joint model compared to other survival models. Finally, some extensions to the model are considered, including a more general non-conjugate mixing distribution, and alternative ways of including explanatory variables in the joint model

Survival models for censored point processes

In studies of recurrent events, there can be a lot of information about a cohort over a period of time, but it may not be possible to extract as much information from the data as would be liked. This thesis considers data on individuals experiencing recurrent events, before and after they are randomised to treatment. The prerandomisation outcome is a period count, while the post-randomisation outcome is a survival time. Standard survival analysis may treat the pre-randomisation period count as a covariate, but it is proposed that point process models will give a more precise estimate of the treatment effect. A joint model is presented, based on a Poisson process with individual frailty. The pre-randomisation seizure counts are distributed as Poisson variables with rate depending on explanatory variables as well as a random frailty. The model for the post-randomisation survival times is the exponential distribution with the same individual seizure rate, modified by a multiplicative treatment effect. A conjugate mixing distribution (frailty) is used, and alternative mixing distributions are also discussed. The model is motivated by and illustrated on individual patient data from five randomised trials of two treatments for epilepsy. The data are presented, and the standard analyses are contrasted with the results of the joint model. This thesis also considers the relative efficiency of the joint model compared to other survival models. Finally, some extensions to the model are considered, including a more general non-conjugate mixing distribution, and alternative ways of including explanatory variables in the joint model.EThOS - Electronic Theses Online ServiceEngineering and Physical Sciences Research Council (EPSRC)GBUnited Kingdo

Estimation of the Health Impact and Cost-Effectiveness of Influenza Vaccination with Enhanced Effectiveness in Canada

INTRODUCTION: The propensity for influenza viruses to mutate and recombine makes them both a familiar threat and a prototype emerging infectious disease. Emerging evidence suggests that the use of MF59-adjuvanted vaccines in older adults and young children enhances protection against influenza infection and reduces adverse influenza-attributable outcomes compared to unadjuvanted vaccines. The health and economic impact of such vaccines in the Canadian population are uncertain. METHODS: We constructed an age-structured compartmental model simulating the transmission of influenza in the Canadian population over a ten-year period. We compared projected health outcomes (quality-adjusted life years (QALY) lost), costs, and incremental cost-effectiveness ratios (ICERs) for three strategies: (i) current use of unadjuvanted trivalent influenza vaccine; (ii) use of MF59-adjuvanted influenza vaccine adults ≥65 in the Canadian population, and (iii) adjuvanted vaccine used in both older adults and children aged < 6. RESULTS: In the base case analysis, use of adjuvanted vaccine in older adults was highly cost-effective (ICER = $2111/QALY gained), but such a program was "dominated" by a program that extended the use of adjuvanted vaccine to include young children (ICER =$1612/QALY). Results were similar whether or not a universal influenza immunization program was used in other age groups; projections were robust in the face of wide-ranging sensitivity analyses. INTERPRETATION: Based on the best available data, it is projected that replacement of traditional trivalent influenza vaccines with MF59-adjuvanted vaccines would confer substantial benefits to vaccinated and unvaccinated individuals, and would be economically attractive relative to other widely-used preventive interventions

Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials

Background Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. Methods A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. Results Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). Conclusions The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy

Trends in Mortality from Septicaemia and Pneumonia with Economic Development: An Age-Period-Cohort Analysis

BackgroundHong Kong population has experienced drastic changes in its economic development in the 1940s. Taking advantage of Hong Kong’s unique demographic and socioeconomic history, characterized by massive, punctuated migration waves from Southern China, and recent, rapid transition from a pre-industrialized society to the first ethnic Chinese community reaching ‘‘first world’’ status over the last 60 years (i.e., in two or three generations), we examined the longitudinal trends in infection related mortality including septicemia compared to trends in non-bacterial pneumonia to generate hypotheses for further testing in other recently transitioned economies and to provide generalized aetiological insights on how economic transition affects infection-related mortality. Methods We used deaths from septicemia and pneumonia not specified as bacterial, and population figures in Hong Kong from 1976–2005. We fitted age-period-cohort models to decompose septicemia and non-bacterial pneumonia mortality rates into age, period and cohort effects. Results Septicaemia-related deaths increased exponentially with age, with a downturn by period. The birth cohort curves had downward inflections in both sexes in the 1940s, with a steeper deceleration for women. Non-bacterial pneumoniarelated deaths also increased exponentially with age, but the birth cohort patterns showed no downturns for those born in the 1940s. Conclusion The observed changes appeared to suggest that better early life conditions may enable better development of adaptive immunity, thus enhancing immunity against bacterial infections, with greater benefits for women than men. Given the interaction between the immune system and the gonadotropic axis, these observations are compatible with the hypothesis that upregulation of the gonadotropic axis underlies some of the changes in disease patterns with economic development

Hundreds of severe pediatric COVID-19 infections in Wuhan prior to the lockdown

Integrative Biolog

The Time Required to Estimate the Case Fatality Ratio of Influenza Using Only the Tip of an Iceberg: Joint Estimation of the Virulence and the Transmission Potential

Estimating the case fatality ratio (CFR) of a novel strain of influenza virus during the early stage of the pandemic is one of key epidemiological tasks to be conducted as rapid research response. Past experience during the epidemics of severe acute respiratory syndrome (SARS) and influenza A (H1N1-2009) posed several technical challenges in estimating the CFR in real time. The present study aimed to develop a simple method to estimate the CFR based on readily available datasets, that is, confirmed cases and deaths, while addressing some of the known technical issues. To assess the reliability and validity of the proposed method, we examined the minimum length of time required for the assigned CFR to be included within the 95% confidence intervals and for the estimated CFR to be below a prespecified cut-off value by means of Monte Carlo simulations. Overall, the smaller the transmission potential was, the longer it took to compare the estimated CFR against the cut-off value. If policymaking and public health response have to be made based on the CFR estimate derived from the proposed method and readily available data, it should be noted that the successful estimation may take longer than a few months

Breast cancer incidence and mortality in a transitioning Chinese population: current and future trends

Background Projections of future trends in cancer incidence and mortality are important for public health planning. Methods By using 1976–2010 data in Hong Kong, we fitted Poisson age-period-cohort models and made projections for future breast cancer incidence and mortality to 2025. Results Age-standardised breast cancer incidence (/mortality) is projected to increase (/decline) from 56.7 (/9.3) in 2011–2015 to 62.5 (/8.6) per 100 000 women in 2021–2025. Conclusions The incidence pattern may relate to Hong Kong’s socio-economic developmental history, while falling mortality trends are, most likely, due to improvements in survival from treatment advancement and improved health service delivery

Using the COVID-19 to influenza ratio to estimate early pandemic spread in Wuhan, China and Seattle, US

Background: Pandemic SARS-CoV-2 was first reported in Wuhan, China on December 31, 2019. Twenty-one days later, the US identified its first case a man who had traveled from Wuhan to the state of Washington. Recent studies in the Wuhan and Seattle metropolitan areas retrospectively tested samples taken from patients with COVID-like symptoms. In the Wuhan study, there were 4 SARS-CoV-2 positives and 7 influenza positives out of 26 adults outpatients who sought care for influenza-like-illness at two central hospitals prior to January 12, 2020. The Seattle study reported 25 SARS-CoV-2 positives and 442 influenza positives out of 2353 children and adults who reported acute respiratory illness prior to March 9, 2020. Here, we use these findings to extrapolate the early prevalence of symptomatic COVID-19 in Wuhan and Seattle. Methods: For each city, we estimate the ratio of COVID-19 to influenza infections from the retrospective testing data and estimate the age-specific prevalence of influenza from surveillance reports during the same time period. Combining these, we approximate the total number of symptomatic COVID-19 infections. Findings: In Wuhan, there were an estimated 1386 [95% CrI: 420 3793] symptomatic cases over 30 of COVID- 19 between December 30, 2019 and January 12, 2020. In Seattle, we estimate that 2268 [95% CrI: 498, 6069] children under 18 and 4367 [95% CrI: 2776, 6526] adults were symptomatically infected between February 24 and March 9, 2020. We also find that the initial pandemic wave in Wuhan likely originated with a single infected case who developed symptoms sometime between October 26 and December 13, 2019; in Seattle, the seeding likely occurred between December 25, 2019 and January 15, 2020. Interpretation: The spread of COVID-19 in Wuhan and Seattle was far more extensive than initially reported. The virus likely spread for months in Wuhan before the lockdown. Given that COVID-19 appears to be overwhelmingly mild in children, our high estimate for symptomatic pediatric cases in Seattle suggests that there may have been thousands more mild cases at the time.We acknowledge support from NIH grant U01 GM087791 and Tito’s Handmade VodkaIntegrative Biolog

Effects of School Closures, 2008 Winter Influenza Season, Hong Kong

In winter 2008, kindergartens and primary schools in Hong Kong were closed for 2 weeks after media coverage indicated that 3 children had died, apparently from influenza. We examined prospective influenza surveillance data before, during, and after the closure. We did not find a substantial effect on community transmission