Time-varying coefficient models for the analysis of air pollution and health outcome data

In this article a time-varying coefficient model is developed to examine the relationship between adverse health and short-term (acute) exposure to air pollution. This model allows the relative risk to evolve over time, which may be due to an interaction with temperature, or from a change in the composition of pollutants, such as particulate matter, over time. The model produces a smooth estimate of these time-varying effects, which are not constrained to follow a fixed parametric form set by the investigator. Instead, the shape is estimated from the data using penalized natural cubic splines. Poisson regression models, using both quasi-likelihood and Bayesian techniques, are developed, with estimation performed using an iteratively re-weighted least squares procedure and Markov chain Monte Carlo simulation, respectively. The efficacy of the methods to estimate different types of time-varying effects are assessed via a simulation study, and the models are then applied to data from four cities that were part of the National Morbidity, Mortality, and Air Pollution Study

On the number of founding germ cells in humans

BACKGROUND: The number of founding germ cells (FGCs) in mammals is of fundamental significance to the fidelity of gene transmission between generations, but estimates from various methods vary widely. In this paper we obtain a new estimate for the value in humans by using a mathematical model of germ cell development that depends on available oocyte counts for adult women. RESULTS: The germline-development model derives from the assumption that oogonial proliferation in the embryonic stage starts with a founding cells at t = 0 and that the subsequent proliferation can be defined as a simple stochastic birth process. It follows that the population size X(t) at the end of germline expansion (around the 5(th )month of pregnancy in humans; t = 0.42 years) is a random variable with a negative binomial distribution. A formula based on the expectation and variance of this random variable yields a moment-based estimate of a that is insensitive to the progressive reduction in oocyte numbers due to their utilization and apoptosis at later stages of life. In addition, we describe an algorithm for computing the maximum likelihood estimation of the FGC population size (a), as well as the rates of oogonial division and loss to apoptosis. Utilizing both of these approaches to evaluate available oocyte-counting data, we have obtained an estimate of a = 2 – 3 for Homo sapiens. CONCLUSION: The estimated number of founding germ cells in humans corresponds well with values previously derived from chimerical or mosaic mouse data. These findings suggest that the large variation in oocyte numbers between individual women is consistent with a smaller founding germ cell population size than has been estimated by cytological analyses

Accumulation of driver and passenger mutations during tumor progression

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a novel mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development - providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate, for the first time, the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small, 0.005 +- 0.0005, and has major implications for experimental cancer research

Quantitative systematic review of the associations between short-term exposure to nitrogen dioxide and mortality and hospital admissions.

BACKGROUND: Short-term exposure to NO₂ has been associated with adverse health effects and there is increasing concern that NO₂ is causally related to health effects, not merely a marker of traffic-generated pollution. No comprehensive meta-analysis of the time-series evidence on NO₂ has been published since 2007. OBJECTIVE: To quantitatively assess the evidence from epidemiological time-series studies published worldwide to determine whether and to what extent short-term exposure to NO₂ is associated with increased numbers of daily deaths and hospital admissions. DESIGN: We conducted a quantitative systematic review of 204 time-series studies of NO₂ and daily mortality and hospital admissions for several diagnoses and ages, which were indexed in three bibliographic databases up to May 2011. We calculated random-effects estimates by different geographic regions and globally, and also tested for heterogeneity and small study bias. RESULTS: Sufficient estimates for meta-analysis were available for 43 cause-specific and age-specific combinations of mortality or hospital admissions (25 for 24 h NO₂ and 18 of the same combinations for 1 h measures). For the all-age group, a 10 µg/m(3) increase in 24 h NO₂ was associated with increases in all-cause, cardiovascular and respiratory mortality (0.71% (95% CI 0.43% to 1.00%), 0.88% (0.63% to 1.13%) and 1.09% (0.75% to 1.42%), respectively), and with hospital admissions for respiratory (0.57% (0.33% to 0.82%)) and cardiovascular (0.66% (0.32% to 1.01%)) diseases. Evidence of heterogeneity between geographical region-specific estimates was identified in more than half of the combinations analysed. CONCLUSIONS: Our review provides clear evidence of health effects associated with short-term exposure to NO₂ although further work is required to understand reasons for the regional heterogeneity observed. The growing literature, incorporating large multicentre studies and new evidence from less well-studied regions of the world, supports further quantitative review to assess the independence of NO₂ health effects from other air pollutants

Does telomere elongation lead to a longer lifespan if cancer is considered?

As cell proliferation is limited due to the loss of telomere repeats in DNA of normal somatic cells during division, telomere attrition can possibly play an important role in determining the maximum life span of organisms as well as contribute to the process of biological ageing. With computer simulations of cell culture development in organisms, which consist of tissues of normal somatic cells with finite growth, we otain an increase of life span and life expectancy for longer telomeric DNA in the zygote. By additionally considering a two-mutation model for carcinogenesis and indefinite proliferation by the activation of telomerase, we demonstrate that the risk of dying due to cancer can outweigh the positive effect of longer telomeres on the longevity.Comment: 9 pages including 5 figure