Patrick Brown

Bio: Patrick Brown is an academic researcher from University of Toronto. The author has contributed to research in topics: Population & Markov chain Monte Carlo. The author has an hindex of 24, co-authored 101 publications receiving 2136 citations. Previous affiliations of Patrick Brown include St. Michael's GAA, Sligo & McMaster University.

Arsenic in drinking water and urinary tract cancers: a systematic review of 30 years of epidemiological evidence.

Abstract: Arsenic in drinking water is a public health issue affecting hundreds of millions of people worldwide. This review summarizes 30 years of epidemiological studies on arsenic exposure in drinking water and the risk of bladder or kidney cancer, quantifying these risks using a meta-analytical framework. Forty studies met the selection criteria. Seventeen provided point estimates of arsenic concentrations in drinking water and were used in a meta-analysis of bladder cancer incidence (7 studies) and mortality (10 studies) and kidney cancer mortality (2 studies). Risk estimates for incidence and mortality were analyzed separately using Generalized Linear Models. Predicted risks for bladder cancer incidence were estimated at 10, 50 and 150 μg/L arsenic in drinking water. Bootstrap randomizations were used to assess robustness of effect size. Twenty-eight studies observed an association between arsenic in drinking water and bladder cancer. Ten studies showed an association with kidney cancer, although of lower magnitude than that for bladder cancer. The meta-analyses showed the predicted risks for bladder cancer incidence were 2.7 [1.2–4.1]; 4.2 [2.1–6.3] and; 5.8 [2.9–8.7] for drinking water arsenic levels of 10, 50, and 150 μg/L, respectively. Bootstrapped randomizations confirmed this increased risk, but, lowering the effect size to 1.4 [0.35–4.0], 2.3 [0.59–6.4], and 3.1 [0.80–8.9]. The latter suggests that with exposures to 50 μg/L, there was an 83% probability for elevated incidence of bladder cancer; and a 74% probability for elevated mortality. For both bladder and kidney cancers, mortality rates at 150 ug/L were about 30% greater than those at 10 μg/L. Arsenic in drinking water is associated with an increased risk of bladder and kidney cancers, although at lower levels (<150 μg/L), there is uncertainty due to the increased likelihood of exposure misclassification at the lower end of the exposure curve. Meta-analyses suggest exposure to 10 μg/L of arsenic in drinking water may double the risk of bladder cancer, or at the very least, increase it by about 40%. With the large number of people exposed to these arsenic concentrations worldwide the public health consequences of arsenic in drinking water are substantial.

Spatial epidemiology and natural population structure of Campylobacter jejuni colonizing a farmland ecosystem.

Abstract: Recent progress in determining the population structure of Campylobacter jejuni, and discerning associations between genotypes and specific niches, has emphasized the shortfall in our understanding of the ecology and epidemiology of this bacterium. We examined the natural structure of the C. jejuni community associated with cattle farmland in the UK by structured spatiotemporal sampling of habitats, including livestock and wild animal faeces, environmental water and soil, over a 10-week period within a 100 km2 area. A total of 172 isolates were characterized using multilocus sequence typing into 65 sequence types (STs). Isolates from cattle faeces were significantly over-represented in the ST-61 complex, whereas isolates from wildlife faeces and water were more likely to belong to the ST-45 complex and a number of unusual STs, many of which were first encountered during this study. Sampling within a narrow spatiotemporal window permitted the application of novel statistical methods exploring the relationship between the genetic relatedness and spatial separation of isolates. This approach showed that isolates from the same sampling squares and squares separated by <1.0 km were genetically more similar than isolates separated by greater distances. Our study demonstrates the potential of multilocus sequence typing combined with spatial modelling in exploring natural transmission pathways for C. jejuni.

Blur‐generated non‐separable space–time models

Abstract: Statistical space–time modelling has traditionally been concerned with separable covariance functions, meaning that the covariance function is a product of a purely temporal function and a purely spatial function. We draw attention to a physical dispersion model which could model phenomena such as the spread of an air pollutant. We show that this model has a non-separable covariance function. The model is well suited to a wide range of realistic problems which will be poorly fitted by separable models. The model operates successively in time: the spatial field at time t +1 is obtained by 'blurring' the field at time t and adding a spatial random field. The model is first introduced at discrete time steps, and the limit is taken as the length of the time steps goes to 0. This gives a consistent continuous model with parameters that are interpretable in continuous space and independent of sampling intervals. Under certain conditions the blurring must be a Gaussian smoothing kernel. We also show that the model is generated by a stochastic differential equation which has been studied by several researchers previously.

Proprotein Convertase Subtilisin Kexin Type 9 Promotes Intestinal Overproduction of Triglyceride-Rich Apolipoprotein B Lipoproteins Through Both Low-Density Lipoprotein Receptor–Dependent and –Independent Mechanisms

Abstract: Background—Proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein (LDL) receptor (LDLR), and its deficiency in humans results in low plasma LDL cholesterol and protection against coronary heart disease. Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor. Here, we studied the effects of physiological levels of PCSK9 on intestinal triglyceride-rich apoB lipoprotein production and elucidated for the first time the cellular and molecular mechanisms involved. Methods and Results—Treatment of human enterocytes (CaCo-2 cells) with recombinant human PCSK9 (10 μg/mL for 24 hours) increased cellular and secreted apoB48 and apoB100 by 40% to 55% each (P<0.01 versus untreated cells), whereas short-term deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to a 1.5-fold increase in apoB mRNA (P<0.01) and to ...

Interspecific Demographic Trade-Offs and Soil-Related Habitat Associations of Tree Species along Resource Gradients

Abstract: Summary 1. Interspecific relationships between fundamental demographic rates, often called demographic trade-offs, emerge from constraints within individuals related to morphology, physiology and resource allocation. Plant species that grow fast in high light usually have high mortality in shade, and this well-established relationship in part defines a species’ successional niche. More generally, this relationship represents a trade-off between a species’ ability to grow quickly to exploit abundant resources vs. avoiding mortality when resources are less plentiful, but few studies have described this demographic trade-off with respect to environmental factors other than light. 2. Using demographic data from 960 tree species in Bornean rain forest, we examined the evidence for an interspecific demographic trade-off between fast growth and low mortality and its variation among habitats defined by variation in soil fertility and moisture. Such a trade-off could contribute to sorting of tree species among habitats and partly explain the striking patterns of species’ edaphic associations in this and other forests. 3. We found strong evidence for this demographic trade-off, both within the same habitat and when growth on edaphically rich habitats was compared with mortality on a habitat with lower below-ground resource availability. 4. The slope of the growth-mortality relationship varied among habitats, being steepest on the habitat lowest in below-ground resources. For species with the fastest potential growth rates, mortality was higher on this habitat than at comparable growth rates on the three more edaphically rich habitats, providing a possible mechanism by which fast-growing species may be eliminated from the poorest habitat. Adaptations for fast growth may entail a greater mortality risk, if inherently fast-growing species fail to maintain a positive C-balance when below-ground resources are scarce. 5. Conversely, for species with the slowest potential growth rates, the highest species’ mortality rates occurred on the habitats with greatest below-ground resource availability, implying that slow-growing species may have a competitive disadvantage in resource-rich environments. 6. Synthesis. Differences among habitats in the steepness of this trade-off may sort species into different habitats along this edaphic gradient, whereas on the same soil, this demographic trade-off could facilitate coexistence of at least some species in this forest. Thus, by generating emergent demographic trade-offs that vary along resource gradients, plant life-history strategies can influence species diversity and distribution.

Forecasting, Structural Time Series Models and the Kalman Filter

Abstract: In this book, Andrew Harvey sets out to provide a unified and comprehensive theory of structural time series models. Unlike the traditional ARIMA models, structural time series models consist explicitly of unobserved components, such as trends and seasonals, which have a direct interpretation. As a result the model selection methodology associated with structural models is much closer to econometric methodology. The link with econometrics is made even closer by the natural way in which the models can be extended to include explanatory variables and to cope with multivariate time series. From the technical point of view, state space models and the Kalman filter play a key role in the statistical treatment of structural time series models. The book includes a detailed treatment of the Kalman filter. This technique was originally developed in control engineering, but is becoming increasingly important in fields such as economics and operations research. This book is concerned primarily with modelling economic and social time series, and with addressing the special problems which the treatment of such series poses. The properties of the models and the methodological techniques used to select them are illustrated with various applications. These range from the modellling of trends and cycles in US macroeconomic time series to to an evaluation of the effects of seat belt legislation in the UK.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: A systematic analysis for the Global Burden of Disease Study 2015

Abstract: BACKGROUND The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING Bill & Melinda Gates Foundation.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Sixth Special Issue

Abstract: The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the Committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Seventh Edition of the JCA Special Issue continues to maintain this methodology and rigor to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Seventh Edition, like its predecessor, has consistently applied the category and grading system definitions in the fact sheets. The general layout and concept of a fact sheet that was used since the fourth edition has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. The Seventh Edition discusses 87 fact sheets (14 new fact sheets since the Sixth Edition) for therapeutic apheresis diseases and medical conditions, with 179 indications, which are separately graded and categorized within the listed fact sheets. Several diseases that are Category IV which have been described in detail in previous editions and do not have significant new evidence since the last publication are summarized in a separate table. The Seventh Edition of the JCA Special Issue serves as a key resource that guides the utilization of therapeutic apheresis in the treatment of human disease. J. Clin. Apheresis 31:149-162, 2016. © 2016 Wiley Periodicals, Inc.