Verifying the fully “Laplacianised” posterior Naïve Bayesian approach and more

Mussa and Glen would like to thank Unilever for financial support, whereas Mussa and Mitchell thank the BBSRC for funding this research through grant BB/I00596X/1. Mitchell thanks the Scottish Universities Life Sciences Alliance (SULSA) for financial support.Background In a recent paper, Mussa, Mitchell and Glen (MMG) have mathematically demonstrated that the “Laplacian Corrected Modified Naïve Bayes” (LCMNB) algorithm can be viewed as a variant of the so-called Standard Naïve Bayes (SNB) scheme, whereby the role played by absence of compound features in classifying/assigning the compound to its appropriate class is ignored. MMG have also proffered guidelines regarding the conditions under which this omission may hold. Utilising three data sets, the present paper examines the validity of these guidelines in practice. The paper also extends MMG’s work and introduces a new version of the SNB classifier: “Tapered Naïve Bayes” (TNB). TNB does not discard the role of absence of a feature out of hand, nor does it fully consider its role. Hence, TNB encapsulates both SNB and LCMNB. Results LCMNB, SNB and TNB performed differently on classifying 4,658, 5,031 and 1,149 ligands (all chosen from the ChEMBL Database) distributed over 31 enzymes, 23 membrane receptors, and one ion-channel, four transporters and one transcription factor as their target proteins. When the number of features utilised was equal to or smaller than the “optimal” number of features for a given data set, SNB classifiers systematically gave better classification results than those yielded by LCMNB classifiers. The opposite was true when the number of features employed was markedly larger than the “optimal” number of features for this data set. Nonetheless, these LCMNB performances were worse than the classification performance achieved by SNB when the “optimal” number of features for the data set was utilised. TNB classifiers systematically outperformed both SNB and LCMNB classifiers. Conclusions The classification results obtained in this study concur with the mathematical based guidelines given in MMG’s paper—that is, ignoring the role of absence of a feature out of hand does not necessarily improve classification performance of the SNB approach; if anything, it could make the performance of the SNB method worse. The results obtained also lend support to the rationale, on which the TNB algorithm rests: handled judiciously, taking into account absence of features can enhance (not impair) the discriminatory classification power of the SNB approach.Publisher PDFPeer reviewe

Application of quality by design concepts and automation to improve manufacturing process consistency of development and clinical-stage cell therapies

Designing manufacturing processes to reproducibly generate process-sensitive human cells of sufficient quantity and quality for clinical application is challenging and complex. Manufacture of cell therapies in manual flask based processes is controlled primarily through adherence to detailed SOPs which may contain subjective user interventions and relatively poorly defined operating controls. This situation can lead to clinical production processes with limited control of critical quality attributes, significant reliance on endpoint quality testing and consequent product wastage. Applying systematic and data driven approaches to process development, many of which form part of the Quality by Design (QbD) toolset, reduces manufacturing process risk. We have applied these approaches with a series of partners and cell types to demonstrate application of QbD tools to cell therapies. This includes statistical capability analysis to define process confidence limits for expansion processes, to identify sources of process variability, and to quantify process performance in relation to the process specification and necessary scale. This further enables risk assessment and gap analysis to identify and prioritise key manufacture process risks with common recurrent elements including input materials, cryo-strategy, and operational parameters pertaining to culture and medium supply strategy. Key variable screening via statistically designed experiments has enabled improvement in process consistency across multiple operations and an improved understanding of process tolerance to parameter levels. It also highlights where automation could be applied to enhance process reproducibility and increase process scale whilst retaining process format with comparability to prior manufacturing development. CompacT SelecT automated manufacturing processes have demonstrated consistently greater cell yields than manual processes with statistical analysis showing significantly improved confidence intervals between multiple production batches and facilitating identification of remaining sources of variation for further targeted process improvement. Example case studies include a partnership with ReNeuron, a UK-based stem cell therapy business currently undergoing a phase II clinical trial with its CTX cell therapy candidate to enhance motor recovery in disabled stroke patients, to develop scalable robust production processes for the CTX cell line

Prospectus, March 8, 2000

https://spark.parkland.edu/prospectus_2000/1008/thumbnail.jp

Clonal Variation In The Quality of Radiata Pine Random Width Boards

This clonal study was undertaken to analyze clonal variation in the quality of random width boards, and to document broad sense heritabilities of the board quality and the associated tree variables in radiata pine (Pinus radiata D. Don). Two individual trees from each often clones were selected based on a wide range of clone mean values for diameter at breast height (DBH), internode index, branch index, and outerwood basic density.Several defect types and frequencies showed differences between clones; variation between clones was greater for defect frequencies than for defect areas. Also differences between clones were greater for boards from unpruned logs than from pruned logs. Knot frequency was far higher in boards coming from the clones with shorter internodes, while knot area per m2 did not vary significantly between clones. Internode length appeared to be highly heritable. The blemish area per m2 from pruned logs was highly variable between clones. Causes and exact configuration of this latter defect are largely unknown and unpredictable but appear to be associated with pruning.Differences were observed in the grade distributions between clones. For all log types, the best performing clone was a large DBH clone with the longest internodes, while a small DBH clone with the shortest internode was the worst. These results show that defect frequency and grades in appearance lumber and associated tree characteristics show high broad sense heritability. This suggests that the grades and the value of these products can be predicted, particularly from tree internode index. A breeding program for long internode radiata pine, started in 1970, has already shown that this trait responds well to selection and breeding

Lack of association between COMT gene and deficit/nondeficit schizophrenia

BACKGROUND: The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val(158)Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states. Schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients. METHODS: Eighty-six schizophrenia cases that met DSM-IV criteria for schizophrenia were recruited. Additional categorization into deficit and nondeficit syndrome was performed using the Schedule for the Deficit Syndrome (SDS). A healthy comparison group (n = 50) matched to cases on age and ethnicity was recruited. Allele and genotype frequencies of the Val(158)Met polymorphism were compared among healthy controls, and schizophrenia cases with the deficit (n = 21), and nondeficit syndrome (n = 65). RESULTS: There was a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls (p = 0.004). No significant differences in allele or genotype frequencies were observed between deficit and nondeficit cases. CONCLUSION: Results from this preliminary analysis failed to show an effect of COMT gene on deficit schizophrenia

Improving the Representativeness of Behavioral and Clinical Surveillance for Persons with HIV in the United States: The Rationale for Developing a Population-Based Approach

The need for a new surveillance approach to understand the clinical outcomes and behaviors of people in care for HIV evolved from the new challenges for monitoring clinical outcomes in the HAART era, the impact of the epidemic on an increasing number of areas in the US, and the need for representative data to describe the epidemic and related resource utilization and needs. The Institute of Medicine recommended that the Centers for Disease Control and Prevention and the Heath Resources and Services Administration coordinate efforts to survey a random sample of HIV-infected persons in care, in order to more accurately measure the need for prevention and care services. The Medical Monitoring Project (MMP) was created to meet these needs. This manuscript describes the evolution and design of MMP, a new nationally representative clinical outcomes and behavioral surveillance system, and describes how MMP data will be used locally and nationally to identify care and treatment utilization needs, and to plan for prevention interventions and services

The Effects of Home Computers on Educational Outcomes: Evidence from a Field Experiment with Schoolchildren

Are home computers are an important input in the educational production function? To address this question, we conduct a field experiment involving the provision of free computers to schoolchildren for home use. Low-income children attending middle and high schools in 15 schools in California were randomly selected to receive free computers and followed over the school year. The results indicate that the experiment substantially increased computer ownership and total computer use among the schoolchildren with no substitution away from use at school or other locations outside the home. We find no evidence that the home computers improved educational outcomes for the treatment group. From detailed administrative data provided by the schools and a follow-up survey, we find no evidence of positive effects on a comprehensive set of outcomes such as grades, test scores, credits, attendance, school enrollment, computer skills, and college aspirations. The estimates also do not indicate that the effects of home computers on educational outcomes are instead negative. Our estimates are precise enough to rule out even modestly-sized positive or negative impacts. The lack of a positive net effect on educational outcomes may be due to displacement from non-educational uses such as for games, social networking, and entertainment. We find evidence that total hours of computer use for games and social networking increases substantially with having a home computer, and increases more than total hours of computer use for schoolwork

Worldwide Prevalence of Lentivirus Infection in Wild Feline Species: Epidemiologic and Phylogenetic Aspects

The natural occurrence of lentiviruses closely related to feline immunodeficiency virus (FIV) in nondomestic felid species is shown here to be worldwide. Cross-reactive antibodies to FIV were common in several free-ranging populations of large cats, including East African lions and cheetahs of the Serengeti ecosystem and in puma (also called cougar or mountain lion) populations throughout North America. Infectious puma lentivirus (PLV) was isolated from several Florida panthers, a severely endangered relict puma subspecies inhabiting the Big Cypress Swamp and Everglades ecosystems in southern Florida. Phylogenetic analysis of PLV genomic sequences from disparate geographic isolates revealed appreciable divergence from domestic cat FIV sequences as well as between PLV sequences found in different North American locales. The level of sequence divergence between PLV and FIV was greater than the level of divergence between human and certain simian immunodeficiency viruses, suggesting that the transmission of FIV between feline species is infrequent and parallels in time the emergence of HIV from simian ancestors

Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour

The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and-unexpectedly-lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractant

Networks, space and organisational performance:a study of the determinants of industrial research income generation by universities

This paper examines the extent to which both network structure and spatial factors impact on the organizational performance of universities as measured by the generation of industrial research income. Drawing on data concerning the interactions of universities in the UK with large research and development (R&D)-intensive firms, the paper employs both social network analysis and regression analysis. It is found that the structural position of a university within networks with large R&D-intensive firms is significantly associated with the level of research income gained from industry. Spatial factors, on the other hand, are not found to be clearly associated with performance, suggesting that universities operate on a level playing field across regional environments once other factors are controlled for