Outcome prediction based on microarray analysis: a critical perspective on methods

<p>Abstract</p> <p>Background</p> <p>Information extraction from microarrays has not yet been widely used in diagnostic or prognostic decision-support systems, due to the diversity of results produced by the available techniques, their instability on different data sets and the inability to relate statistical significance with biological relevance. Thus, there is an urgent need to address the statistical framework of microarray analysis and identify its drawbacks and limitations, which will enable us to thoroughly compare methodologies under the same experimental set-up and associate results with confidence intervals meaningful to clinicians. In this study we consider gene-selection algorithms with the aim to reveal inefficiencies in performance evaluation and address aspects that can reduce uncertainty in algorithmic validation.</p> <p>Results</p> <p>A computational study is performed related to the performance of several gene selection methodologies on publicly available microarray data. Three basic types of experimental scenarios are evaluated, i.e. the independent test-set and the 10-fold cross-validation (CV) using maximum and average performance measures. Feature selection methods behave differently under different validation strategies. The performance results from CV do not mach well those from the independent test-set, except for the support vector machines (SVM) and the least squares SVM methods. However, these wrapper methods achieve variable (often low) performance, whereas the hybrid methods attain consistently higher accuracies. The use of an independent test-set within CV is important for the evaluation of the predictive power of algorithms. The optimal size of the selected gene-set also appears to be dependent on the evaluation scheme. The consistency of selected genes over variation of the training-set is another aspect important in reducing uncertainty in the evaluation of the derived gene signature. In all cases the presence of outlier samples can seriously affect algorithmic performance.</p> <p>Conclusion</p> <p>Multiple parameters can influence the selection of a gene-signature and its predictive power, thus possible biases in validation methods must always be accounted for. This paper illustrates that independent test-set evaluation reduces the bias of CV, and case-specific measures reveal stability characteristics of the gene-signature over changes of the training set. Moreover, frequency measures on gene selection address the algorithmic consistency in selecting the same gene signature under different training conditions. These issues contribute to the development of an objective evaluation framework and aid the derivation of statistically consistent gene signatures that could eventually be correlated with biological relevance. The benefits of the proposed framework are supported by the evaluation results and methodological comparisons performed for several gene-selection algorithms on three publicly available datasets.</p

The nucleus reuniens: a key node in the neurocircuitry of stress and depression

Uncorrected proofThe hippocampus and prefrontal cortex (PFC) are connected in a reciprocal manner: whereas the hippocampus projects directly to the PFC, a polysynaptic pathway that passes through the nucleus reuniens (RE) of the thalamus relays inputs from the PFC to the hippocampus. The present study demonstrates that lesioning and/or inactivation of the RE reduces coherence in the PFC-hippocampal pathway, provokes an antidepressant-like behavioral response in the forced swim test and prevents, but does not ameliorate, anhedonia in the chronic mild stress (CMS) model of depression. Additionally, RE lesioning before CMS abrogates the well-known neuromorphological and endocrine correlates of CMS. In summary, this work highlights the importance of the reciprocal connectivity between the hippocampus and PFC in the establishment of stress-induced brain pathology and suggests a role for the RE in promoting resilience to depressive illness.Greece for providing sertraline. This work was supported by an ‘Education and Lifelong Learning, Supporting Postdoctoral Researchers’, co-financed by the European Social Fund (ESF) and the General Secretariat for Research and Technology, Greece, the Life and Health Sciences Research Institute (ICVS), ON.2—O NOVO NORTE—North Portugal Regional Operational Program 2007/2013 of the National Strategic Reference Framework (NSRF) 2007/2013 through the European Regional Development Fund (ERDF), the Portuguese Foundation for Science and Technology (FCT; grant no. NMC-113934) and an InEurope program funded by International Brain Research Organizationinfo:eu-repo/semantics/publishedVersio

The pattern of locomotor activity after cocaine treatment in the rat

The present study used a computerised technique to assess the behavioural effects on locomotor activity of i.p. cocaine administration in the rat. This computerised method provides considerable information about various behavioural responses, as well as accuracy by measuring the frequency and duration of every behavioural event. Cocaine induced an increase in behavioural events related to motor activity, such as moving, sniffing and rearing, while standing was reduced. Cocaine increased the frequency of the behavioural responses recorded, but decreased their mean duration. No stereotyped behavioural element, such as head swinging, head bobbing, licking, stereotyped mouth moving or stereotyped sniffing, was recorded after cocaine treatment. Cocaine, unlike d-amphetamine, induced a specific behavioural pattern characterised predominantly at all doses by a stimulated motor activation involving an increase in moving and sniffing and a decrease in standing behaviour

Differential alterations in basal and D-amphetamine-induced behavioural pattern following 6-OHDA or ibotenic acid lesions into the dorsal striatum

It is well known that the corpus striatum is related to the sterotyped activation induced by several psychostimulants. In this study we analyzed the effects of 6-OHDA, in comparison with those of ibotenic acid lesions, into the dorsal striatum, on the behavioural pattern induced by saline or D-amphetamine treatment. A computerized technique for recording the animal motor activity was developed in order to define in a detailed way the behavioural profile in lesioned and sham-operated rats induced by the saline or D-amphetamine treatment. A 6-OHDA lesion into the dorsal striatum modified the basal behavioural pattern which was mainly characterized by reduced motor activation while ibotenic acid lesion affected the structure of the basal behavioral pattern. D-Amphetamine administration in 6-OHDA lesioned rats induced a behavioural stimulation, but a decreased motor and stereotyped activation was observed compared to the sham-operated animals treated with D-amphetamine. In contrast, D-amphetamine administration in the ibotenic acid-lesioned rats induced a motor and stereotyped activity which was not reduced compared to that seen after D-amphetamine treatment in sham-operated rats. These results suggest that these two types of lesion induced differential effects on the behavioural pattern either after saline or after D-amphelamine administration. Dopaminergic neurotransmission in the dorsal striatum plays a permissive role on the emergence of the behavioural responses, while the dorsal striatum circuitry plays a crucial role on the organization of the behavioural pattern. In addition, dopaminergic activity in this structure serves a primary control in the D-amphetamine-elicited motor activation or stereotypy, while the striatal structure is involved in the shaping of the D-amphetamine behavioural pattern. (C) 1998 Elsevier Science B.V. All rights reserved

Comparative Transcriptome Analysis of Two Olive Cultivars in Response to NaCl-Stress

Background: Olive (Olea europaea L.) cultivation is rapidly expanding and low quality saline water is often used for irrigation. The molecular basis of salt tolerance in olive, though, has not yet been investigated at a system level. In this study a comparative transcriptomics approach was used as a tool to unravel gene regulatory networks underlying salinity response in olive trees by simulating as much as possible olive growing conditions in the field. Specifically, we investigated the genotype-dependent differences in the transcriptome response of two olive cultivars, a salt-tolerant and a salt-sensitive one. Methodology/Principal Findings: A 135-day long salinity experiment was conducted using one-year old trees exposed to NaCl stress for 90 days followed by 45 days of post-stress period during the summer. A cDNA library made of olive seedling mRNAs was sequenced and an olive microarray was constructed. Total RNA was extracted from root samples after 15, 45 and 90 days of NaCl-treatment as well as after 15 and 45 days of post-treatment period and used for microarray hybridizations. SAM analysis between the NaCl-stress and the post-stress time course resulted in the identification of 209 and 36 differentially expressed transcripts in the salt–tolerant and salt–sensitive cultivar, respectively. Hierarchical clustering revealed two major, distinct clusters for each cultivar. Despite the limited number of probe sets, transcriptional regulatory networks were constructed for both cultivars while several hierarchically-clustered interacting transcription factor regulators such as JERF and bZIP homologues were identified. Conclusions/Significance: A systems biology approach was used and differentially expressed transcripts as well as regulatory interactions were identified. The comparison of the interactions among transcription factors in olive with those reported for Arabidopsis might indicate similarities in the response of a tree species with Arabidopsis at the transcriptional level under salinity stress

d-amphetamine, cocaine and caffeine: A comparative study of acute effects on locomotor activity and behavioural patterns in rats

Although open-field behaviour has been considered a valid and reliable index of locomotor activity in rodents, the simple measures traditionally recorded in this test do not readily allow for differentiation between compounds of the same general class, e.g. psychostimulants. The present methodology was developed to facilitate detailed and continuous observations on the behaviour of drug-treated rats. In addition to an automated (photocell) measure of general locomotor activity, ethological techniques were used to record the frequency and duration of standing, moving, sniffing, rearing, grooming, scratching, sniffing air, freezing, head-swinging and licking. A series of factor analyses was also performed in order to further characterize treatment-induced changes in the structure of behaviour. Compounds studied were d-amphetamine (0.5, 1.5, 3, 6 mg/kg), cocaine (5, 10, 20, 50 mg/kg) and caffeine (5, 10, 20, 40 mg/kg). Although all three psychostimulants increased the automated measure of general locomotor activity, cocaine (which produced the largest effects) monotonically increased general activity over the dose range tested, whereas the stimulant effects of the other two compounds were either reduced (d-amphetamine) or eliminated (caffeine) at higher doses. More detailed observations provided confirmation of the differences in effect produced by these compounds. For example, the frequency and duration of &apos;moving&apos; dose-dependently increased after cocaine, while d-amphetamine and caffeine again produced bell-shaped dose-response curves. However, whereas low-intermediate doses of d- amphetamine reduced the mean duration of moving, sniffing and rearing, no such effect was observed at the highest dose tested. This finding, together with the appearance of licking in the behavioural repertoire, suggests a stereotyped character to responses seen at high doses of this compound, though neither cocaine nor caffeine induced stereotypy. As factor analyses also revealed quite different behavioural structures associated with these three drugs, present findings demonstrate that detailed observation of behaviour represents a useful approach to research on the behavioural pharmacology of psychostimulants

A proposal for gene Signature integration

Summarization: Gene expression patterns that can distinguish to a clinically significant degree disease subclasses not only play a prominent role in diagnosis but also lead to therapeutic strategies that tailor treatment to the particular biology of each disease. Nevertheless, gene expression signatures derived through statistical feature identification procedures on population datasets have received rightful criticism, since they share only few genes in common for a particular pathology, even if they derived from the same dataset using different methodologies. An optimistic view to this problem emerging from the wealth of biological interactions is that a statistical solution may not be unique. The derived signatures may be complementary parts of a global one, with each individual signature intersecting only a small part of biological evidence. In this work we focus on the biological knowledge hidden behind different gene signatures and propose a methodology for integrating such knowledge towards retrieving a unified signature.Παρουσιάστηκε στο: 9th International Conference on nformation Technology and Applications in Biomedicin