13 research outputs found
Beyond the Scope of Free-Wilson Analysis: Building Interpretable QSAR Models with Machine Learning Algorithms
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
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
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 StructureâActivity Relationship ModelingîžQuantifying Prediction Uncertainty
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
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.ĂndĂ„ 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 Ă
ke 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 Ă
ke Malmberg och landsantikvarien Gunnar Svahnström. I boken publiceringskostnaderna har ekonomiskt bidrag lÀmnats av Gotlands kommun och RiksantikvarieÀmbetet.Boken har redigerats av Sture BalgÄrd och Ann Mari Westerlind med hjÀlp av Henrik O Andersson, Bo Ek, Göran Lindahl, Fredrik von Platen, John Sjöström Gunnar Westerlind och Hans Wetterfors.Skeppsholmen, Stockholm, sommaren 1973.Arkitekturskolans lÀrare och elever.Konsthögskolans arkitekturskola i Stockholm har under lÀsÄret 1972/73 studerat bevarande - och förnyelseproblem i Visby. Staden innanför murarna har naturligt nog utgjort tyngdpunkten i arbetet - den hÀr inte bara historiskt och estetiskt fÀngslande utan erbjuder ocksÄ ovanliga möjligheter att trÀnga in i frÄgor, som annars sÀllan har en sÄ klar och renodlad karaktÀr. </p