Ozone and Mortality: A Meta-Analysis of Time-Series Studies and Comparison to a Multi-City Study (The National Morbidity, Mortality, and Air Pollution Study)

While many time-series studies of ozone and daily mortality identified positive associations,others yielded null or inconclusive results. We performed a meta-analysis of 144 effect estimates from 39 time-series studies, and estimated pooled effects by lags, age groups,cause-specific mortality, and concentration metrics. We compared results to estimates from the National Morbidity, Mortality, and Air Pollution Study (NMMAPS), a time-series study of 95 large U.S. cities from 1987 to 2000. Both meta-analysis and NMMAPS results provided strong evidence of a short-term association between ozone and mortality, with larger effects for cardiovascular and respiratory mortality, the elderly, and current day ozone exposure as compared to other single day lags. In both analyses, results were not sensitive to adjustment for particulate matter and model specifications. In the meta-analysis we found that a 10 ppb increase in daily ozone is associated with a 0.83 (95% confidence interval: 0.53, 1.12%) increase in total mortality, whereas the corresponding NMMAPS estimate is 0.25%(0.12, 0.39%). Meta-analysis results were consistently larger than those from NMMAPS,indicating publication bias. Additional publication bias is evident regarding the choice of lags in time-series studies, and the larger heterogeneity in posterior city-specific estimates in the meta-analysis, as compared with NMAMPS.

A unified approach to modeling multivariate binary data using copulas over partitions

Many seemingly disparate approaches for marginal modeling have been developed in recent years. We demonstrate that many current approaches for marginal modeling of correlated binary outcomes produce likelihoods that are equivalent to the proposed copula-based models herein. These general copula models of underlying latent threshold random variables yield likelihood based models for marginal fixed effects estimation and interpretation in the analysis of correlated binary data. Moreover, we propose a nomenclature and set of model relationships that substantially elucidates the complex area of marginalized models for binary data. A diverse collection of didactic mathematical and numerical examples are given to illustrate concepts.

Reduced Bayesian Hierarchical Models: Estimating Health Effects of Simultaneous Exposure to Multiple Pollutants

Quantifying the health effects associated with simultaneous exposure to many air pollutants is now a research priority of the US EPA. Bayesian hierarchical models (BHM) have been extensively used in multisite time series studies of air pollution and health to estimate health effects of a single pollutant adjusted for potential confounding of other pollutants and other time-varying factors. However, when the scientific goal is to estimate the impacts of many pollutants jointly, a straightforward application of BHM is challenged by the need to specify a random-effect distribution on a high-dimensional vector of nuisance parameters, which often do not have an easy interpretation. In this paper we introduce a new BHM formulation, which we call "reduced BHM", aimed at analyzing clustered data sets in the presence of a large number of random effects that are not of primary scientific interest. At the first stage of the reduced BHM, we calculate the integrated likelihood of the parameter of interest (e.g. excess number of deaths attributed to simultaneous exposure to high levels of many pollutants). At the second stage, we specify a flexible random-effect distribution directly on the parameter of interest. The reduced BHM overcomes many of the challenges in the specification and implementation of full BHM in the context of a large number of nuisance parameters. In simulation studies we show that the reduced BHM performs comparably to the full BHM in many scenarios, and even performs better in some cases. Methods are applied to estimate location-specific and overall relative risks of cardiovascular hospital admissions associated with simultaneous exposure to elevated levels of particulate matter and ozone in 51 US counties during the period 1999-2005.

Impact factor statistics and publication practice: What can we learn? (Editorial)

Peer review procedures and citation statistics are important yet often neglected components of the scientific publication process. Here I discuss fundamental consequences of such quality measures for the scientific community and propose three remedial actions: (1) use of a ''Combined Impact Estimate'' as a measure of citation statistics, (2) adoption of an open reviewing policy and (3) acceleration of the publication process in order to raise the reputation of the entire discipline (in our case: behavioural science). Authors, reviewers and editors are invited to contribute to the improvement of publication practice.

Osteoporosis case finding in the general practice: phalangeal radiographic absorptiometry with and without risk factors for osteoporosis to select postmenopausal women eligible for lumbar spine and hip densitometry

Mass screening for osteoporosis using DXA measurements at the spine and hip is presently not recommended by health authorities. Instead, risk factor questionnaires and peripheral bone measurements may facilitate the selection of women eligible for axial bone densitometry. The aim of this study was to validate a case finding strategy for postmenopausal women who would benefit most from subsequent DXA measurement by using phalangeal radiographic absorptiometry (RA) alone or in combination with risk factors in a general practice setting. The sensitivity and specificity of this strategy in detecting osteoporosis (T-score < or =2.5 SD at the spine and/or the hip) were compared with those of the current reimbursement criteria for DXA measurements in Switzerland. Four hundred and twenty-three postmenopausal women with one or more risk factors for osteoporosis were recruited by 90 primary care physicians who also performed the phalangeal RA measurements. All women underwent subsequent DXA measurement of the spine and the hip at the Osteoporosis Policlinic of the University Hospital of Berne. They were allocated to one of two groups depending on whether they matched with the Swiss reimbursement conditions for DXA measurement or not. Logistic regression models were used to predict the likelihood of osteoporosis versus "no osteoporosis" and to derive ROC curves for the various strategies. Differences in the areas under the ROC curves (AUC) were tested for significance. In women lacking reimbursement criteria, RA achieved a significantly larger AUC (0.81; 95% CI 0.72-0.89) than the risk factors associated with patients' age, height and weight (0.71; 95% C.I. 0.62-0.80). Furthermore, in this study, RA provided a better sensitivity and specificity in identifying women with underlying osteoporosis than the currently accepted criteria for reimbursement of DXA measurement. In the Swiss environment, RA is a valid case finding tool for patients with risk factors for osteoporosis, especially for those who do not qualify for DXA reimbursement.

Radiological anatomy of the obturator nerve and its articular branches: basis to develop a method of radiofrequency denervation for hip joint pain

OBJECTIVE: A previous study of radiofrequency neurotomy of the articular branches of the obturator nerve for hip joint pain produced modest results. Based on an anatomical and radiological study, we sought to define a potentially more effective radiofrequency method. DESIGN: Ten cadavers were studied, four of them bilaterally. The obturator nerve and its articular branches were marked by wires. Their radiological relationship to the bone structures on fluoroscopy was imaged and analyzed. A magnetic resonance imaging (MRI) study was undertaken on 20 patients to determine the structures that would be encountered by the radiofrequency electrode during different possible percutaneous approaches. RESULTS: The articular branches of the obturator nerve vary in location over a wide area. The previously described method of denervating the hip joint did not take this variation into account. Moreover, it approached the nerves perpendicularly. Because optimal coagulation requires electrodes to lie parallel to the nerves, a perpendicular approach probably produced only a minimal lesion. In addition, MRI demonstrated that a perpendicular approach is likely to puncture femoral vessels. Vessel puncture can be avoided if an oblique pass is used. Such an approach minimizes the angle between the target nerves and the electrode, and increases the likelihood of the nerve being captured by the lesion made. Multiple lesions need to be made in order to accommodate the variability in location of the articular nerves. CONCLUSIONS: The method that we described has the potential to produce complete and reliable nerve coagulation. Moreover, it minimizes the risk of penetrating the great vessels. The efficacy of this approach should be tested in clinical trials.

The accuracy of FAST in relation to grade of solid organ injuries: a retrospective analysis of 226 trauma patients with liver or splenic lesion

BACKGROUND: This study investigated the role of a negative FAST in the diagnostic and therapeutic algorithm of multiply injured patients with liver or splenic lesions. METHODS: A retrospective analysis of 226 multiply injured patients with liver or splenic lesions treated at Bern University Hospital, Switzerland. RESULTS: FAST failed to detect free fluid or organ lesions in 45 of 226 patients with spleen or liver injuries (sensitivity 80.1%). Overall specificity was 99.5%. The positive and negative predictive values were 99.4% and 83.3%. The overall likelihood ratios for a positive and negative FAST were 160.2 and 0.2. Grade III-V organ lesions were detected more frequently than grade I and II lesions. Without the additional diagnostic accuracy of a CT scan, the mean ISS of the FAST-false-negative patients would be significantly underestimated and 7 previously unsuspected intra-abdominal injuries would have been missed. CONCLUSION: FAST is an expedient tool for the primary assessment of polytraumatized patients to rule out high grade intra-abdominal injuries. However, the low overall diagnostic sensitivity of FAST may lead to underestimated injury patterns and delayed complications may occur. Hence, in hemodynamically stable patients with abdominal trauma, an early CT scan should be considered and one must be aware of the potential shortcomings of a "negative FAST".

Coupling of mutated Met variants to DNA repair via Abl and Rad51

Abnormal activation of DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems is a compelling likelihood with significant implications in both cancer biology and treatment. Here, we show that due to a potential substrate switch, mutated variants of the receptor for hepatocyte growth factor Met, but not the wild-type form of the receptor, directly couple to the Abl tyrosine kinase and the Rad51 recombinase, two key signaling elements of homologous recombination-based DNA repair. Treatment of cells that express the mutated receptor variants with the Met inhibitor SU11274 leads, in a mutant-dependent manner, to a reduction of tyrosine phosphorylated levels of Abl and Rad51, impairs radiation-induced nuclear translocation of Rad51, and acts as a radiosensitizer together with the p53 inhibitor pifithrin-alpha by increasing cellular double-strand DNA break levels following exposure to ionizing radiation. Finally, we propose that in order to overcome a mutation-dependent resistance to SU11274, this aberrant molecular axis may alternatively be targeted with the Abl inhibitor, nilotinib.

Ultraviolet digital imaging of volcanic plumes : implementation and application to magmatic processes at basaltic volcanoes

Magmatic volatiles play a crucial role in volcanism, from magma production at depth to generation of seismic phenomena to control of eruption style. Accordingly, many models of volcano dynamics rely heavily on behavior of such volatiles. Yet measurements of emission rates of volcanic gases have historically been limited, which has restricted model verification to processes on the order of days or longer. UV cameras are a recent advancement in the field of remote sensing of volcanic SO2 emissions. They offer enhanced temporal and spatial resolution over previous measurement techniques, but need development before they can be widely adopted and achieve the promise of integration with other geophysical datasets. Large datasets require a means by which to quickly and efficiently use imagery to calculate emission rates. We present a suite of programs designed to semi-automatically determine emission rates of SO2 from series of UV images. Extraction of high temporal resolution SO2 emission rates via this software facilitates comparison of gas data to geophysical data for the purposes of evaluating models of volcanic activity and has already proven useful at several volcanoes. Integrated UV camera and seismic measurements recorded in January 2009 at Fuego volcano, Guatemala, provide new insight into the system’s shallow conduit processes. High temporal resolution SO2 data reveal patterns of SO2 emission rate relative to explosions and seismic tremor that indicate tremor and degassing share a common source process. Progressive decreases in emission rate appear to represent inhibition of gas loss from magma as a result of rheological stiffening in the upper conduit. Measurements of emission rate from two closely-spaced vents, made possible by the high spatial resolution of the camera, help constrain this model. UV camera measurements at Kilauea volcano, Hawaii, in May of 2010 captured two occurrences of lava filling and draining within the summit vent. Accompanying high lava stands were diminished SO2 emission rates, decreased seismic and infrasonic tremor, minor deflation, and slowed lava lake surface velocity. Incorporation of UV camera data into the multi-parameter dataset gives credence to the likelihood of shallow gas accumulation as the cause of such events.

Systematic review of the empirical evidence of study publication bias and outcome reporting bias

BACKGROUND: The increased use of meta-analysis in systematic reviews of healthcare interventions has highlighted several types of bias that can arise during the completion of a randomised controlled trial. Study publication bias has been recognised as a potential threat to the validity of meta-analysis and can make the readily available evidence unreliable for decision making. Until recently, outcome reporting bias has received less attention. METHODOLOGY/PRINCIPAL FINDINGS: We review and summarise the evidence from a series of cohort studies that have assessed study publication bias and outcome reporting bias in randomised controlled trials. Sixteen studies were eligible of which only two followed the cohort all the way through from protocol approval to information regarding publication of outcomes. Eleven of the studies investigated study publication bias and five investigated outcome reporting bias. Three studies have found that statistically significant outcomes had a higher odds of being fully reported compared to non-significant outcomes (range of odds ratios: 2.2 to 4.7). In comparing trial publications to protocols, we found that 40-62% of studies had at least one primary outcome that was changed, introduced, or omitted. We decided not to undertake meta-analysis due to the differences between studies. CONCLUSIONS: Recent work provides direct empirical evidence for the existence of study publication bias and outcome reporting bias. There is strong evidence of an association between significant results and publication; studies that report positive or significant results are more likely to be published and outcomes that are statistically significant have higher odds of being fully reported. Publications have been found to be inconsistent with their protocols. Researchers need to be aware of the problems of both types of bias and efforts should be concentrated on improving the reporting of trials.

Genetic association studies under the population stratification, family pedigree and application to genome-wide association studies

This dissertation has three separate parts: the first part deals with the general pedigree association testing incorporating continuous covariates; the second part deals with the association tests under population stratification using the conditional likelihood tests; the third part deals with the genome-wide association studies based on the real rheumatoid arthritis (RA) disease data sets from Genetic Analysis Workshop 16 (GAW16) problem 1. Many statistical tests are developed to test the linkage and association using either case-control status or phenotype covariates for family data structure, separately. Those univariate analyses might not use all the information coming from the family members in practical studies. On the other hand, the human complex disease do not have a clear inheritance pattern, there might exist the gene interactions or act independently. In part I, the new proposed approach MPDT is focused on how to use both the case control information as well as the phenotype covariates. This approach can be applied to detect multiple marker effects. Based on the two existing popular statistics in family studies for case-control and quantitative traits respectively, the new approach could be used in the simple family structure data set as well as general pedigree structure. The combined statistics are calculated using the two statistics; A permutation procedure is applied for assessing the p-value with adjustment from the Bonferroni for the multiple markers. We use simulation studies to evaluate the type I error rates and the powers of the proposed approach. Our results show that the combined test using both case-control information and phenotype covariates not only has the correct type I error rates but also is more powerful than the other existing methods. For multiple marker interactions, our proposed method is also very powerful. Selective genotyping is an economical strategy in detecting and mapping quantitative trait loci in the genetic dissection of complex disease. When the samples arise from different ethnic groups or an admixture population, all the existing selective genotyping methods may result in spurious association due to different ancestry distributions. The problem can be more serious when the sample size is large, a general requirement to obtain sufficient power to detect modest genetic effects for most complex traits. In part II, I describe a useful strategy in selective genotyping while population stratification is present. Our procedure used a principal component based approach to eliminate any effect of population stratification. The paper evaluates the performance of our procedure using both simulated data from an early study data sets and also the HapMap data sets in a variety of population admixture models generated from empirical data. There are one binary trait and two continuous traits in the rheumatoid arthritis dataset of Problem 1 in the Genetic Analysis Workshop 16 (GAW16): RA status, AntiCCP and IgM. To allow multiple traits, we suggest a set of SNP-level F statistics by the concept of multiple-correlation to measure the genetic association between multiple trait values and SNP-specific genotypic scores and obtain their null distributions. Hereby, we perform 6 genome-wide association analyses using the novel one- and two-stage approaches which are based on single, double and triple traits. Incorporating all these 6 analyses, we successfully validate the SNPs which have been identified to be responsible for rheumatoid arthritis in the literature and detect more disease susceptibility SNPs for follow-up studies in the future. Except for chromosome 13 and 18, each of the others is found to harbour susceptible genetic regions for rheumatoid arthritis or related diseases, i.e., lupus erythematosus. This topic is discussed in part III.

How to avoid clean intermittent catheterization in men with ileal bladder substitution

PURPOSE: In male patients with ileal bladder substitute we ascertained the likelihood of spontaneous voiding failure, the corrective procedures required and the eventual outcomes. MATERIALS AND METHODS: Following cystectomy and ileal bladder substitution for urothelial cancer between April 1985 and September 2002 male patients were identified and analyzed from the prospective departmental database. Four patients underwent ileum conduit conversion following urethral recurrence or pouch necrosis and were excluded from study. Funnel-shaped outlets were avoided during bladder substitute surgery after the first 4 patients with this configuration experienced voiding failure and required corrective procedures. Only patients with a minimum 5-year followup were assessed for voiding failure, corrective procedures and final outcomes. RESULTS: Of 354 patients with a median age of 65 years (range 36 to 84) treated with bladder substitute 180 (51%) were alive at 5 years. All 180 of these patients spontaneously voided within 3 months of surgery. During this 5-year observation period 22 (12%) patients experienced voiding problems requiring de-obstructive procedures. Following intervention 177 (98%) patients were spontaneously voiding by 5 years. Of 237 patients 77 (32%) were alive at 10 years. Of these 77 patients followed for another 5 years 10 (13%) had similar voiding problems requiring de-obstructive procedures. Subsequently 74 (96%) were voiding spontaneously by 10 years. CONCLUSIONS: Patients often fail to void spontaneously after ileal bladder substitution. However, if a funnel-shaped outlet is avoided and de-obstructive surgery is appropriately implemented, excellent long-term results are seen with spontaneous voiding and clean intermittent catheterization can be avoided.

Application of MFBD Algorithms to Image Reconstruction Under Anisoplanatic Conditions

All optical systems that operate in or through the atmosphere suffer from turbulence induced image blur. Both military and civilian surveillance, gun-sighting, and target identification systems are interested in terrestrial imaging over very long horizontal paths, but atmospheric turbulence can blur the resulting images beyond usefulness. My dissertation explores the performance of a multi-frame-blind-deconvolution technique applied under anisoplanatic conditions for both Gaussian and Poisson noise model assumptions. The technique is evaluated for use in reconstructing images of scenes corrupted by turbulence in long horizontal-path imaging scenarios and compared to other speckle imaging techniques. Performance is evaluated via the reconstruction of a common object from three sets of simulated turbulence degraded imagery representing low, moderate and severe turbulence conditions. Each set consisted of 1000 simulated, turbulence degraded images. The MSE performance of the estimator is evaluated as a function of the number of images, and the number of Zernike polynomial terms used to characterize the point spread function. I will compare the mean-square-error (MSE) performance of speckle imaging methods and a maximum-likelihood, multi-frame blind deconvolution (MFBD) method applied to long-path horizontal imaging scenarios. Both methods are used to reconstruct a scene from simulated imagery featuring anisoplanatic turbulence induced aberrations. This comparison is performed over three sets of 1000 simulated images each for low, moderate and severe turbulence-induced image degradation. The comparison shows that speckle-imaging techniques reduce the MSE 46 percent, 42 percent and 47 percent on average for low, moderate, and severe cases, respectively using 15 input frames under daytime conditions and moderate frame rates. Similarly, the MFBD method provides, 40 percent, 29 percent, and 36 percent improvements in MSE on average under the same conditions. The comparison is repeated under low light conditions (less than 100 photons per pixel) where improvements of 39 percent, 29 percent and 27 percent are available using speckle imaging methods and 25 input frames and 38 percent, 34 percent and 33 percent respectively for the MFBD method and 150 input frames. The MFBD estimator is applied to three sets of field data and the results presented. Finally, a combined Bispectrum-MFBD Hybrid estimator is proposed and investigated. This technique consistently provides a lower MSE and smaller variance in the estimate under all three simulated turbulence conditions.

INSTANTANEOUS PHOTOSYNTHETIC RESPONSE TO TEMPERATURE OF MATURE FOREST CANOPIES AND EXPERIMENTALLY WARMED SEEDLINGS

Tropical trees have been shown to be more susceptible to warming compared to temperate species, and have shown growth and photosynthetic declines at elevated temperatures as little as 3oC above ambient. However, regional and global vegetation models lack the data needed to accurately represent physiological response to increased temperatures in tropical forests. We compared the instantaneous photosynthetic responses to elevated temperatures of four mature tropical rainforest tree species in Puerto Rico and the temperate broadleaf species sugar maple (Acer saccharum) in Michigan. Contrary to expectations, leaves in the upper canopy of both temperate and tropical forests had temperature optima that are already exceeded by mean daily leaf temperatures. This indicates that tropical and temperate forests are already seeing photosynthesis decline at mid-day temperature. This decline may worsen as air temperatures rise with climate change if trees are unable to acclimate, increasing the likelihood that forests may shift from carbon sinks to sources. A secondary study was conducted on experimentally warmed sugar maple seedlings to determine if photosynthesis had been able to acclimate to +5oC air temperature over four years. Species abundance models had predicted a decline of sugar maple within the Upper Peninsula of Michigan over the next 100 years, due to elevated temperature and altered precipitation. Instantaneous photosynthetic temperature response curves on both control and heated seedlings showed that the differences between treatments were not statistically significant, though there was a 16% increase in temperature optima and a 3% increase in maximum rates of photosynthesis in warmed plots. Though evidence of acclimation was not significant, the seedlings did not fare poorly as the models suggest.