152 research outputs found
Combining explainable machine learning, demographic and multi-omic data to inform precision medicine strategies for inflammatory bowel disease.
Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, affect several million individuals worldwide. These diseases are heterogeneous at the clinical, immunological and genetic levels and result from complex host and environmental interactions. Investigating drug efficacy for IBD can improve our understanding of why treatment response can vary between patients. We propose an explainable machine learning (ML) approach that combines bioinformatics and domain insight, to integrate multi-modal data and predict inter-patient variation in drug response. Using explanation of our models, we interpret the ML models' predictions to infer unique combinations of important features associated with pharmacological responses obtained during preclinical testing of drug candidates in ex vivo patient-derived fresh tissues. Our inferred multi-modal features that are predictive of drug efficacy include multi-omic data (genomic and transcriptomic), demographic, medicinal and pharmacological data. Our aim is to understand variation in patient responses before a drug candidate moves forward to clinical trials. As a pharmacological measure of drug efficacy, we measured the reduction in the release of the inflammatory cytokine TNFα from the fresh IBD tissues in the presence/absence of test drugs. We initially explored the effects of a mitogen-activated protein kinase (MAPK) inhibitor; however, we later showed our approach can be applied to other targets, test drugs or mechanisms of interest. Our best model predicted TNFα levels from demographic, medicinal and genomic features with an error of only 4.98% on unseen patients. We incorporated transcriptomic data to validate insights from genomic features. Our results showed variations in drug effectiveness (measured by ex vivo assays) between patients that differed in gender, age or condition and linked new genetic polymorphisms to patient response variation to the anti-inflammatory treatment BIRB796 (Doramapimod). Our approach models IBD drug response while also identifying its most predictive features as part of a transparent ML precision medicine strategy
Application of pharmacogenomics and bioinformatics to exemplify the utility of human <i>ex vivo</i> organoculture models in the field of precision medicine
Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response
Measurement of the W+W-gamma Cross Section and Direct Limits on Anomalous Quartic Gauge Boson Couplings at LEP
The process e+e- -> W+W-gamma is analysed using the data collected with the
L3 detector at LEP at a centre-of-mass energy of 188.6GeV, corresponding to an
integrated luminosity of 176.8pb^-1. Based on a sample of 42 selected W+W-
candidates containing an isolated hard photon, the W+W-gamma cross section,
defined within phase-space cuts, is measured to be: sigma_WWgamma = 290 +/- 80
+/- 16 fb, consistent with the Standard Model expectation. Including the
process e+e- -> nu nu gamma gamma, limits are derived on anomalous
contributions to the Standard Model quartic vertices W+W- gamma gamma and W+W-Z
gamma at 95% CL: -0.043 GeV^-2 < a_0/Lambda^2 < 0.043 GeV^-2 0.08 GeV^-2 <
a_c/Lambda^2 < 0.13 GeV^-2 0.41 GeV^-2 < a_n/Lambda^2 < 0.37 GeV^-2
Production of Single W Bosons at \sqrt{s}=189 GeV and Measurement of WWgamma Gauge Couplings
Single W boson production in electron-positron collisions is studied with the
L3 detector at LEP. The data sample collected at a centre-of-mass energy of
\sqrt{s} = 188.7GeV corresponds to an integrated luminosity of 176.4pb^-1.
Events with a single energetic lepton or two acoplanar hadronic jets are
selected. Within phase-space cuts, the total cross-section is measured to be
0.53 +/- 0.12 +/- 0.03 pb, consistent with the Standard Model expectation.
Including our single W boson results obtained at lower \sqrt{s}, the WWgamma
gauge couplings kappa_gamma and lambda_gamma are determined to be kappa_gamma =
0.93 +/- 0.16 +/- 0.09 and lambda_gamma = -0.31 +0.68 -0.19 +/- 0.13
Search for an invisibly decaying Higgs boson in e^+e^- collisions at \sqrt{s} = 183 - 189 GeV
A search for a Higgs boson decaying into invisible particles is performed
using the data collected at LEP by the L3 experiment at centre-of-mass energies
of 183 GeV and 189 GeV. The integrated luminosities are respectively 55.3 pb^-1
and 176.4 pb^-1. The observed candidates are consistent with the expectations
from Standard Model processes. In the hypothesis that the production cross
section of this Higgs boson equals the Standard Model one and the branching
ratio into invisible particles is 100%, a lower mass limit of 89.2 GeV is set
at 95% confidence level
Search for Neutral Higgs Bosons of the Minimal Supersymmetric Standard Model in e+e- Interactions at \sqrt{s} = 189 GeV
A search for the lightest neutral scalar and neutral pseudoscalar Higgs
bosons in the Minimal Supersymmetric Standard Model is performed using 176.4
pb^-1 of integrated luminosity collected by L3 at a center-of-mass energy of
189 GeV. No signal is observed, and the data are consistent with the expected
Standard Model background. Lower limits on the masses of the lightest neutral
scalar and pseudoscalar Higgs bosons are given as a function of tan(beta).
Lower mass limits for tan(beta)>1 are set at the 95% confidence level to be m_h
> 77.1 GeV and m_A > 77.1 GeV
Measurement of Bose-Einstein Correlations in e+e- -> W+W- at root(s)=189GeV
We investigate Bose-Einstein correlations (BEC) in W-pair production at
root(s)=189GeV using the L3 detector at LEP. We observe BEC between particles
from a single W decay in good agreement with those from a light-quark Z decay
sample. We investigate their possible existence between particles coming from
different W's. No evidence for such inter-W BEC is found
Measurement of the Lifetime of the Tau Lepton
The tau lepton lifetime is measured with the L3 detector at LEP using the
complete data taken at centre-of-mass energies around the Z pole resulting in
tau_tau = 293.2 +/- 2.0 (stat) +/- 1.5 (syst) fs. The comparison of this result
with the muon lifetime supports lepton universality of the weak charged current
at the level of six per mille. Assuming lepton universality, the value of the
strong coupling constant, alpha_s is found to be alpha_s(m_tau^2) = 0.319 +/-
0.015(exp.) +/- 0.014 (theory)
Search for Extra Dimensions in Boson and Fermion Pair Production in e+e- Interactions at LEP
Extra spatial dimensions are proposed by recent theories that postulate the
scale of gravity to be of the same order as the electroweak scale. A sizeable
interaction between gravitons and Standard Model particles is then predicted.
Effects of these new interactions in boson and fermion pair production are
searched for in the data sample collected at centre-of-mass energies above the
Z pole by the L3 detector at LEP. In addition, the direct production of a
graviton associated with a Z boson is investigated. No statistically
significant hints for the existence of these effects are found and lower limits
in excess of 1 TeV are derived on the scale of this new theory of gravity
Measurement of the Probability of Gluon Splitting into Charmed Quarks in Hadronic Z Decays
We have measured the probability, n(g->cc~), of a gluon splitting into a
charm-quark pair using 1.7 million hadronic Z decays collected by the L3
detector. Two independent methods have been applied to events with a three-jet
topology. One method relies on tagging charmed hadrons by identifying a lepton
in the lowest energy jet. The other method uses a neural network based on
global event shape parameters. Combining both methods, we measure n(g->cc~)=
[2.45 +/- 0.29 +/- 0.53]%
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