Collectives of diagnostic biomarkers identify high-risk subpopulations of hematuria patients: exploiting heterogeneity in large-scale biomarker data

Background: Ineffective risk stratification can delay diagnosis of serious disease in patients with hematuria. We applied a systems biology approach to analyze clinical, demographic and biomarker measurements (n = 29) collected from 157 hematuric patients: 80 urothelial cancer (UC) and 77 controls with confounding pathologies.

Methods: On the basis of biomarkers, we conducted agglomerative hierarchical clustering to identify patient and biomarker clusters. We then explored the relationship between the patient clusters and clinical characteristics using Chi-square analyses. We determined classification errors and areas under the receiver operating curve of Random Forest Classifiers (RFC) for patient subpopulations using the biomarker clusters to reduce the dimensionality of the data.

Results: Agglomerative clustering identified five patient clusters and seven biomarker clusters. Final diagnoses categories were non-randomly distributed across the five patient clusters. In addition, two of the patient clusters were enriched with patients with ‘low cancer-risk’ characteristics. The biomarkers which contributed to the diagnostic classifiers for these two patient clusters were similar. In contrast, three of the patient clusters were significantly enriched with patients harboring ‘high cancer-risk” characteristics including proteinuria, aggressive pathological stage and grade, and malignant cytology. Patients in these three clusters included controls, that is, patients with other serious disease and patients with cancers other than UC. Biomarkers which contributed to the diagnostic classifiers for the largest ‘high cancer- risk’ cluster were different than those contributing to the classifiers for the ‘low cancer-risk’ clusters. Biomarkers which contributed to subpopulations that were split according to smoking status, gender and medication were different.

Conclusions: The systems biology approach applied in this study allowed the hematuric patients to cluster naturally on the basis of the heterogeneity within their biomarker data, into five distinct risk subpopulations. Our findings highlight an approach with the promise to unlock the potential of biomarkers. This will be especially valuable in the field of diagnostic bladder cancer where biomarkers are urgently required. Clinicians could interpret risk classification scores in the context of clinical parameters at the time of triage. This could reduce cystoscopies and enable priority diagnosis of aggressive diseases, leading to improved patient outcomes at reduced costs. © 2013 Emmert-Streib et al; licensee BioMed Central Ltd.

Path-Dependency, Stocks, Switching Points, Flows: Reflections on Long-term Global Change and Local Opportunities

This paper examines the possibilities for peripheral localities to achieve upward mobility in the world-system by “hooking on” to larger processes of world-system accumulation. In particular, is it possible for economies that are dependent on foreign investment to receive a flow of investments that is high enough to overcome the negative impacts of a high stock of foreign investment, thus enabling them to cross a threshold and achieve upward mobility in the world-system? An analysis of therecent experience of the southern Irish “Celtic Tiger” economy during 1990-2000 indicates that such an upward movement is possible on the basis of massive foreign investment inflows. On closer examination, however, the Irish-type model appears to be highly deficient, because a high proportion of growth is illusionary and also on grounds of social desirability and lack of generalizability.

“Islands” in Holocene forests: implications for forest openness, landscape clearance and “culture-steppe” species

Human activity has undoubtedly had a major impact on Holocene forested ecosystems, with the concurrent expansion of plants and animals associated with cleared landscapes and pasture, also known as 'culture-steppe'. However, this anthropogenic perspective may have underestimated the contribution of autogenic disturbance (e.g. wind-throw, fire), or a mixture of autogenic and anthropogenic processes, within early Holocene forests. Entomologists have long argued that the north European primary forest was probably similar in structure to pasture woodland. This idea has received support from the conservation biologist Frans Vera, who has recently strongly argued that the role of large herbivores in maintaining open forests in the primeval landscapes of Europe has been seriously underestimated. This paper reviews this debate from a fossil invertebrate perspective and looks at several early Holocene insect assemblages. Although wood taxa are indeed important during this period, species typical of open areas and grassland and dung beetles, usually associated with the dung of grazing animals, are persistent presences in many early woodland faunas. We also suggest that fire and other natural disturbance agents appear to have played an important ecological role in some of these forests, maintaining open areas and creating open vegetation islands within these systems. More work, however, is required to ascertain the role of grazing animals, but we conclude that fossil insects have a significant contribution to make to this debate. This evidence has fundamental implications in terms of how the palaeoecological record is interpreted, particularly by environmental archaeologists and palaeoecologists who may be more interested in identifying human-environment interactions rather than the ecological processes which may be preserved within palaeoecological records.

The Holocene British and Irish ancient woodland fossil beetle fauna: implications for forest history, biodiversity and faunal colonisation

This paper presents a new review of our knowledge of the ancient forest beetle fauna from Holocene archaeological and palaeoecological sites in Great Britain and Ireland. It examines the colonisation, dispersal and decline of beetle species, highlighting the scale and nature of human activities in the shaping of the landscape of the British Isles. In particular, the paper discusses effects upon the insect fauna, and examines in detail the fossil record from the Humberhead Levels, eastern England. It discusses the local extirpation of up to 40 species in Britain and 15 species in Ireland. An evaluation of the timing of extirpations is made, suggesting that many species in Britain disappear from the fossil record between c. 3000 cal BC and 1000 cal BC (c. 5000-3000 cal BP), although some taxa may well have survived until considerably later. In Ireland, there are two distinct trends, with a group of species which seem to be absent after c. 2000 cal BC (c. 4000 cal BP) and a further group which survives until at least as late as the medieval period. The final clearance of the Irish landscape over the last few hundred years was so dramatic, however, that some species which are not especially unusual in a British context were decimated. Reasons behind the extirpation of taxa are examined in detail, and include a combination of forest clearance and human activities, isolation of populations, lack of temporal continuity of habitats, edaphic and competition factors affecting distribution of host trees (particularly pine), lack of forest fires and a decline in open forest systems. The role of climate change in extirpations is also evaluated. Consideration is given to the significance of these specialised ancient forest inhabitants in Ireland in the absence of an early Holocene land-bridge which suggests that colonisation was aided by other mechanisms, such as human activities and wood-rafting. Finally, the paper discusses the Continental origins of the British and Irish fauna and its hosts and the role played by European glacial refugia.

Polymer conditioning of alum sludge and discrepancies between estimates of the optimum dosage

The paper outlines the effects of polymer conditioning on alum sludge properties, such as floc size, density, fractal dimension (DF) and rheological properties. Experimental results demonstrate that polymer conditioning of alum sludge leads to: larger floc size with a plateau reached in higher doses; higher densities associated with higher doses; increased degree of compactness; and an initial decrease followed by an increase of supernatant viscosity with continued increase in polymer dose. The secondary focus of this paper dwells on a comparison of the estimates of optimum dose using different criteria that emanate from established dewatering tests such as CST, SRF, liquid phase viscosity and modified SRF as well as a simple settlement test in terms of CML30. Alum sludge was derived from a water works treating coloured, low-turbidity raw waters.

Path-integral study of a two-dimensional Lennard-Jones glass

The glass transition in a quantum Lennard-Jones mixture is investigated by constant-volume path-integral simulations. Particles are assumed to be distinguishable, and the strength of quantum effects is varied by changing h from zero (the classical case) to one (corresponding to a highly quantum-mechanical regime). Quantum delocalization and zero point energy drastically reduce the sensitivity of structural and thermodynamic properties to the glass transition. Nevertheless, the glass transition temperature T-g can be determined by analyzing the phase space mobility of path-integral centroids. At constant volume, the T-g of the simulated model increases monotonically with increasing h. Low temperature tunneling centers are identified, and the quantum versus thermal character of each center is analyzed. The relation between these centers and soft quasilocalized harmonic vibrations is investigated. Periodic minimizations of the potential energy with respect to the positions of the particles are performed to determine the inherent structure of classical and quantum glassy samples. The geometries corresponding to these energy minima are found to be qualitatively similar in all cases. Systematic comparisons for ordered and disordered structures, harmonic and anharmonic dynamics, classical and quantum systems show that disorder, anharmonicity, and quantum effects are closely interlinked.

Simultaneous histories, path sums, and measurements for noncommuting variables

We analyze von Neumann-like quantum measurements in terms of simultaneous virtual paths constructed for two noncommuting variables. The approach is applied to measurements of operator functions of conjugate variables and to the joint measurements of such variables. The limits of applicability of the restricted phase space path integral are studied. We demonstrate that, for a simple joint measurement, using entangled meter states allows one to manipulate the order in which the measurements are conducted. The effects of '' weakening '' a measurement by choosing unsharp meter states are also discussed.