13 research outputs found

    Beyond the Scope of Free-Wilson Analysis: Building Interpretable QSAR Models with Machine Learning Algorithms

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    A novel methodology was developed to build Free-Wilson like local QSAR models by combining R-group signatures and the SVM algorithm. Unlike Free-Wilson analysis this method is able to make predictions for compounds with R-groups not present in a training set. Eleven public data sets were chosen as test cases for comparing the performance of our new method with several other traditional modeling strategies, including Free-Wilson analysis. Our results show that the R-group signature SVM models achieve better prediction accuracy compared with Free-Wilson analysis in general. Moreover, the predictions of R-group signature models are also comparable to the models using ECFP6 fingerprints and signatures for the whole compound. Most importantly, R-group contributions to the SVM model can be obtained by calculating the gradient for R-group signatures. For most of the studied data sets, a significant correlation with that of a corresponding Free-Wilson analysis is shown. These results suggest that the R-group contribution can be used to interpret bioactivity data and highlight that the R-group signature based SVM modeling method is as interpretable as Free-Wilson analysis. Hence the signature SVM model can be a useful modeling tool for any drug discovery project

    Beyond the Scope of Free-Wilson Analysis: Building Interpretable QSAR Models with Machine Learning Algorithms

    No full text
    A novel methodology was developed to build Free-Wilson like local QSAR models by combining R-group signatures and the SVM algorithm. Unlike Free-Wilson analysis this method is able to make predictions for compounds with R-groups not present in a training set. Eleven public data sets were chosen as test cases for comparing the performance of our new method with several other traditional modeling strategies, including Free-Wilson analysis. Our results show that the R-group signature SVM models achieve better prediction accuracy compared with Free-Wilson analysis in general. Moreover, the predictions of R-group signature models are also comparable to the models using ECFP6 fingerprints and signatures for the whole compound. Most importantly, R-group contributions to the SVM model can be obtained by calculating the gradient for R-group signatures. For most of the studied data sets, a significant correlation with that of a corresponding Free-Wilson analysis is shown. These results suggest that the R-group contribution can be used to interpret bioactivity data and highlight that the R-group signature based SVM modeling method is as interpretable as Free-Wilson analysis. Hence the signature SVM model can be a useful modeling tool for any drug discovery project

    Using conformal prediction to prioritize compound synthesis in drug discovery

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    The choice of how much money and resources to spend to understand certain problems is of high interest in many areas. This work illustrates how computational models can be more tightly coupled with experiments to generate decision data at lower cost without reducing the quality of the decision. Several different strategies are explored to illustrate the trade off between lowering costs and quality in decisions. AUC is used as a performance metric and the number of objects that can be learnt from is constrained. Some of the strategies described reach AUC values over 0.9 and outperforms strategies that are more random. The strategies that use conformal predictor p-values show varying results, although some are top performing. The application studied is taken from the drug discovery process. In the early stages of this process compounds, that potentially could become marketed drugs, are being routinely tested in experimental assays to understand the distribution and interactions in humans

    Conformal Regression for Quantitative Structure–Activity Relationship ModelingQuantifying Prediction Uncertainty

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    Making predictions with an associated confidence is highly desirable as it facilitates decision making and resource prioritization. Conformal regression is a machine learning framework that allows the user to define the required confidence and delivers predictions that are guaranteed to be correct to the selected extent. In this study, we apply conformal regression to model molecular properties and bioactivity values and investigate different ways to scale the resultant prediction intervals to create as efficient (i.e., narrow) regressors as possible. Different algorithms to estimate the prediction uncertainty were used to normalize the prediction ranges, and the different approaches were evaluated on 29 publicly available data sets. Our results show that the most efficient conformal regressors are obtained when using the natural exponential of the ensemble standard deviation from the underlying random forest to scale the prediction intervals, but other approaches were almost as efficient. This approach afforded an average prediction range of 1.65 pIC50 units at the 80% confidence level when applied to bioactivity modeling. The choice of nonconformity function has a pronounced impact on the average prediction range with a difference of close to one log unit in bioactivity between the tightest and widest prediction range. Overall, conformal regression is a robust approach to generate bioactivity predictions with associated confidence

    Visby Innerstad : En anvÀndningsplan

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    Sedan lĂ„ng tid föreligger i stort sett enighet om att bevara innerstadens bebyggelse och att anpassa eventuella nytillskott till det redan bestĂ„ende. Med den instĂ€llningen har förĂ€ndringsprocessen bĂ„de dĂ€mpats och mildrats men Ă€ndĂ„ inte bragts att avstanna. FörĂ€ndringar sker stĂ€ndigt om det ocksĂ„ huvudsakligen i smĂ„tt: de mĂ„nga synbart sĂ„ ansprĂ„kslösa byggnadsĂ„tgĂ€rderna adderar efterhand ihop sig till nĂ„got större och mer genomgripande. LĂ„ngsamt, nĂ€stan omĂ€rkligt, Ă€ndrar innerstaden sitt ansikte.ÄndĂ„ Ă€r det inte sjĂ€lva husen som förĂ€ndrats mest utan anvĂ€ndningen av dem. Ur funktionell synpunkt har 1950 - och 60-talen har varit nĂ„got av en omstörtning i innerstadens historia: den har förlorat nĂ€stan hĂ€lften av de boende, en stor del av detaljhandeln och praktiskt taget helt sin gamla roll som skolcentrum. I gengĂ€ld har ytterstaden vuxit ut till ett sammanhĂ€ngande kilometerbrett bĂ€lte. Till stor del av denna funktionella förĂ€ndring en följd av beslutet att bevara innerstadens bebyggelse. Vad som inte fĂ„tt plats inom den gamla ramen har etablerats utandör den.Föreliggande arbete vill ge en översiktlig bild av förĂ€ndringsförloppen, sedda i ett lĂ„ngt tidsperspektiv men med tonvikt pĂ„ dagslĂ€get. Bebyggelsen tas upp till utförlig granskning men ocksĂ„ anvĂ€ndningen av den. Det Ă€r just samspelet mellan husen och de funtkioner, de fyller, som kan sĂ€gas utgöra bokens huvudtema. I de flesta fall Ă€r detta sammanhang hus-anvĂ€ndning alldeles konfliktfritt och föranleder dĂ€rför inte heller nĂ„gon diskussion. Vad som behandlas Ă€r de relativt fĂ„ problematiska fallen, hus som borde rustas upp för att fylla sin uppgift, hus som Ă€r olĂ€mpligt nyttjade eller inte anvĂ€nda alls. En serie sĂ„dana fall tas upp till systematisk genomgĂ„ng; samtidigt berörs ocksĂ„ de trafik - och miljömĂ€ssiga konsekvenserna. Bokens syfte Ă€r alltsĂ„ klart: den ger ett underlag av fakta för arbetet med att jĂ€mka samman byggnader och anvĂ€ndningsformer. I den meningen kan skriften kallas en anvĂ€dningsplan för Visby innanför murarna.Arkitekturskolanas arbete har bedrivitis parallellt med den kommunala InnerstadskommittĂ©ns verksamhet. NĂ„got organiserat samarbete har inte förekommit med de informella kontakterna har varit bĂ„de tĂ€ta och goda. Att likheterna mellan InnerstadskommittĂ©n och Arkitekturskolans slutsatser blivit sĂ„ pass stora, kan tillskrivas en gemensam helhetssyn.En av Arkitekturskolans elever, arkitekt Lars-Ingvar Larsson, har tidigare sjĂ€lvstĂ€ndigt genomfört en undersökning av förĂ€ndringar i innerstaden 1945-70- Denna studie publicerats separat och bör uppfattas som ett komplement till den hör föreliggande.Förutom de i innehĂ„llsförteckningen nĂ€mnda har ytterligare nĂ„gra aktivt medverkat i arbetet. Studiet av trafikfrĂ„gorna i innerstaden, i hamnen och öster om ringmuren leddes av Åke Claesson, I fĂ€ltstudier och diskussioner medverkande Göran MĂ„nsson.Arkitekturskolan har fĂ„tt god hjĂ€lp av ett antal initierade personer i Visby. SĂ€rskild tacksamhet Ă€r vi skyldiga byggnadsnĂ€mnden ordförande Henning Jacobson, kommunalrĂ„det C B Stenström, stadsarkitekten MĂ„ns Hagbergm f. lĂ€nsbostadsdorektören Åke Malmberg och landsantikvarien Gunnar Svahnström. I boken publiceringskostnaderna har ekonomiskt bidrag lĂ€mnats av Gotlands kommun och RiksantikvarieĂ€mbetet.Boken har redigerats av Sture BalgĂ„rd och Ann Mari Westerlind med hjĂ€lp av Henrik O Andersson, Bo Ek, Göran Lindahl, Fredrik von Platen, John Sjöström Gunnar Westerlind och Hans Wetterfors.Skeppsholmen, Stockholm, sommaren 1973.Arkitekturskolans lĂ€rare och elever.Konsthögskolans arkitekturskola i Stockholm har under lĂ€sĂ„ret 1972/73 studerat bevarande - och förnyelseproblem i Visby. Staden innanför murarna har naturligt nog utgjort tyngdpunkten i arbetet - den hĂ€r inte bara historiskt och estetiskt fĂ€ngslande utan erbjuder ocksĂ„ ovanliga möjligheter att trĂ€nga in i frĂ„gor, som annars sĂ€llan har en sĂ„ klar och renodlad karaktĂ€r. </p
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