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Target Fishing: A Single-Label or Multi-Label Problem?
According to Cobanoglu et al and Murphy, it is now widely acknowledged that the single target paradigm (one protein or target, one disease, one drug) that has been the dominant premise in drug development in the recent past is untenable. More often than not, a drug-like compound (ligand) can be promiscuous - that is, it can interact with more than one target protein. In recent years, in in silico target prediction methods the promiscuity issue has been approached computationally in different ways. In this study we confine attention to the so-called ligand-based target prediction machine learning approaches, commonly referred to as target-fishing. With a few exceptions, the target-fishing approaches that are currently ubiquitous in cheminformatics literature can be essentially viewed as single-label multi-classification schemes; these approaches inherently bank on the single target paradigm assumption that a ligand can home in on one specific target. In order to address the ligand promiscuity issue, one might be able to cast target-fishing as a multi-label multi-class classification problem. For illustrative and comparison purposes, single-label and multi-label Naive Bayes classification models (denoted here by SMM and MMM, respectively) for target-fishing were implemented. The models were constructed and tested on 65,587 compounds and 308 targets retrieved from the ChEMBL17 database. SMM and MMM performed differently: for 16,344 test compounds, the MMM model returned recall and precision values of 0.8058 and 0.6622, respectively; the corresponding recall and precision values yielded by the SMM model were 0.7805 and 0.7596, respectively. However, at a significance level of 0.05 and one degree of freedom McNemar test performed on the target prediction results returned by SMM and MMM for the 16,344 test ligands gave a chi-squared value of 15.656, in favour of the MMM approach
Methodological criteria for the assessment of moderators in systematic reviews of randomised controlled trials : a consensus study
Background: Current methodological guidelines provide advice about the assessment of sub-group analysis within
RCTs, but do not specify explicit criteria for assessment. Our objective was to provide researchers with a set of
criteria that will facilitate the grading of evidence for moderators, in systematic reviews.
Method: We developed a set of criteria from methodological manuscripts (n = 18) using snowballing technique,
and electronic database searches. Criteria were reviewed by an international Delphi panel (n = 21), comprising
authors who have published methodological papers in this area, and researchers who have been active in the
study of sub-group analysis in RCTs. We used the Research ANd Development/University of California Los Angeles
appropriateness method to assess consensus on the quantitative data. Free responses were coded for consensus
and disagreement. In a subsequent round additional criteria were extracted from the Cochrane Reviewers’
Handbook, and the process was repeated.
Results: The recommendations are that meta-analysts report both confirmatory and exploratory findings for subgroups
analysis. Confirmatory findings must only come from studies in which a specific theory/evidence based apriori
statement is made. Exploratory findings may be used to inform future/subsequent trials. However, for
inclusion in the meta-analysis of moderators, the following additional criteria should be applied to each study:
Baseline factors should be measured prior to randomisation, measurement of baseline factors should be of
adequate reliability and validity, and a specific test of the interaction between baseline factors and interventions
must be presented.
Conclusions: There is consensus from a group of 21 international experts that methodological criteria to assess
moderators within systematic reviews of RCTs is both timely and necessary. The consensus from the experts
resulted in five criteria divided into two groups when synthesising evidence: confirmatory findings to support
hypotheses about moderators and exploratory findings to inform future research. These recommendations are
discussed in reference to previous recommendations for evaluating and reporting moderator studies
Evaluation of machine-learning methods for ligand-based virtual screening
Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed
Are people who participate in cultural activities more satisfied with life?
The influence of various aspects of life on wellbeing has been extensively researched. However, despite little empirical evidence, participation in leisure activities has been assumed to increase subjective wellbeing. Leisure is important because it is more under personal control than other sources of life satisfaction. This study asked whether people who participate in cultural leisure activities have higher life satisfaction than people who do not, if different types of leisure have the same influence on life satisfaction and if satisfaction is dependent on the frequency of participation or the number of activities undertaken. It used data from UKHLS Survey to establish associations between type, number and frequency of participation in leisure activities and life satisfaction. Results showed an independent and positive association of participation in sport, heritage and active-creative leisure activities and life satisfaction but not for participation in popular entertainment, theatre hobbies and museum/galleries. The association of reading hobbies and sedentary-creative activities and life satisfaction was negative. High life satisfaction was associated with engaging in a number of different activities rather than the frequency of participation in each of them. The results have implications for policy makers and leisure services providers, in particular those associated with heritage recreation. Subjective wellbeing measures, such as life satisfaction, and not economic measures alone should be considered in the evaluation of services. The promotion of leisure activities which are active and promote social interaction should be considered in programmes aimed at improving the quality of life
A Visual Metaphor Describing Neural Dynamics in Schizophrenia
Background: In many scientific disciplines the use of a metaphor as an heuristic aid is not uncommon. A well known example in somatic medicine is the 'defense army metaphor' used to characterize the immune system. In fact, probably a large part of the everyday work of doctors consists of 'translating' scientific and clinical information (i.e. causes of disease, percentage of succes versus risk of side-effects) into information tailored to the needs and capacities of the individual patient. The ability to do so in an effective way is at least partly what makes a clinician a good communicator. Schizophrenia is a severe psychiatric disorder which affects approximately 1% of the population. Over the last two decades a large amount of molecular-biological, imaging and genetic data have been accumulated regarding the biological underpinnings of schizophrenia. However, it remains difficult to understand how the characteristic symptoms of schizophrenia such as hallucinations and delusions are related to disturbances on the molecular-biological level. In general, psychiatry seems to lack a conceptual framework with sufficient explanatory power to link the mental- and molecular-biological domains. Methodology/Principal Findings: Here, we present an essay-like study in which we propose to use visualized concepts stemming from the theory on dynamical complex systems as a 'visual metaphor' to bridge the mental- and molecular-biological domains in schizophrenia. We first describe a computer model of neural information processing; we show how the information processing in this model can be visualized, using concepts from the theory on complex systems. We then describe two computer models which have been used to investigate the primary theory on schizophrenia, the neurodevelopmental model, and show how disturbed information processing in these two computer models can be presented in terms of the visual metaphor previously described. Finally, we describe the effects of dopamine neuromodulation, of which disturbances have been frequently described in schizophrenia, in terms of the same visualized metaphor. Conclusions/Significance: The conceptual framework and metaphor described offers a heuristic tool to understand the relationship between the mental- and molecular-biological domains in an intuitive way. The concepts we present may serve to facilitate communicatio
Galaxy Harassment and the Evolution of Clusters of Galaxies
Disturbed spiral galaxies with high rates of star formation pervaded clusters
of galaxies just a few billion years ago, but nearby clusters exclude spirals
in favor of ellipticals. ``Galaxy harassment" (frequent high speed galaxy
encounters) drives the morphological transformation of galaxies in clusters,
provides fuel for quasars in subluminous hosts and leaves detectable debris
arcs. Simulated images of harassed galaxies are strikingly similar to the
distorted spirals in clusters at observed by the Hubble Space
Telescope.Comment: Submitted to Nature. Latex file, 7 pages, 10 photographs in gif and
jpeg format included. 10 compressed postscript figures and text available
using anonymous ftp from ftp://ftp-hpcc.astro.washington.edu/pub/hpcc/moore/
(mget *) Also available at http://www-hpcc.astro.washington.edu/papers
Moyal star product approach to the Bohr-Sommerfeld approximation
The Bohr-Sommerfeld approximation to the eigenvalues of a one-dimensional
quantum Hamiltonian is derived through order (i.e., including the
first correction term beyond the usual result) by means of the Moyal star
product. The Hamiltonian need only have a Weyl transform (or symbol) that is a
power series in , starting with , with a generic fixed point in
phase space. The Hamiltonian is not restricted to the kinetic-plus-potential
form. The method involves transforming the Hamiltonian to a normal form, in
which it becomes a function of the harmonic oscillator Hamiltonian.
Diagrammatic and other techniques with potential applications to other normal
form problems are presented for manipulating higher order terms in the Moyal
series.Comment: 27 pages, no figure
Secular Evolution and the Formation of Pseudobulges in Disk Galaxies
We review internal processes of secular evolution in galaxy disks,
concentrating on the buildup of dense central features that look like
classical, merger-built bulges but that were made slowly out of disk gas. We
call these pseudobulges. As an existence proof, we review how bars rearrange
disk gas into outer rings, inner rings, and gas dumped into the center. In
simulations, this gas reaches high densities that plausibly feed star
formation. In the observations, many SB and oval galaxies show central
concentrations of gas and star formation. Star formation rates imply plausible
pseudobulge growth times of a few billion years. If secular processes built
dense central components that masquerade as bulges, can we distinguish them
from merger-built bulges? Observations show that pseudobulges retain a memory
of their disky origin. They have one or more characteristics of disks: (1)
flatter shapes than those of classical bulges, (2) large ratios of ordered to
random velocities indicative of disk dynamics, (3) small velocity dispersions,
(4) spiral structure or nuclear bars in the bulge part of the light profile,
(5) nearly exponential brightness profiles, and (6) starbursts. These
structures occur preferentially in barred and oval galaxies in which secular
evolution should be rapid. So the cleanest examples of pseudobulges are
recognizable. Thus a large variety of observational and theoretical results
contribute to a new picture of galaxy evolution that complements hierarchical
clustering and merging.Comment: 92 pages, 21 figures in 30 Postscript files; to appear in Annual
Review of Astronomy and Astrophysics, Vol. 42, 2004, in press; for a version
with full resolution figures, see
http://chandra.as.utexas.edu/~kormendy/ar3ss.htm
Networked buffering: a basic mechanism for distributed robustness in complex adaptive systems
A generic mechanism - networked buffering - is proposed for the generation of robust traits in complex systems. It requires two basic conditions to be satisfied: 1) agents are versatile enough to perform more than one single functional role within a system and 2) agents are degenerate, i.e. there exists partial overlap in the functional capabilities of agents. Given these prerequisites, degenerate systems can readily produce a distributed systemic response to local perturbations. Reciprocally, excess resources related to a single function can indirectly support multiple unrelated functions within a degenerate system. In models of genome:proteome mappings for which localized decision-making and modularity of genetic functions are assumed, we verify that such distributed compensatory effects cause enhanced robustness of system traits. The conditions needed for networked buffering to occur are neither demanding nor rare, supporting the conjecture that degeneracy may fundamentally underpin distributed robustness within several biotic and abiotic systems. For instance, networked buffering offers new insights into systems engineering and planning activities that occur under high uncertainty. It may also help explain recent developments in understanding the origins of resilience within complex ecosystems. \ud
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