Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration

Performance of classification systems for age-related macular degeneration in the rotterdam study

Purpose: To compare frequently used classification systems for age-related macular degeneration(AMD) in their abilty to predictlate AMD. Methods:Intotal,9066participantsfromthepopulation-basedRotterdamStudywere followedupforprogressionofAMDduringastudyperiodupto30years.AMDlesions weregradedoncolorfundusphotographsafterconfirmationonotherimagemodalities andgroupedatbaselineaccordingtosixclassificationsystems.LateAMDwasdefinedas geographicatrophyorchoroidalneovascularization.Incidencerate(IR)andcumulative incidence(CuI)oflateAMDwerecalculated,andKaplan-Meierplotsandareaunderthe operating characteristics curves(AUCs)wereconstructed. Results: A total of 186 persons developed incident late AMD during a mean follow-up timeof8.7years.TheAREDSsimplifiedscaleshowedthehighestIRforlateAMDat104 cases/1000 py for ages 75 years. The 3-Continent harmonization classification provided the most stable progression. Drusen area >10% ETDRS grid (hazard ratio 30.05, 95% confidence interval [CI] 19.25–46.91) was most prognostic of progression. The highest AUC of late AMD (0.8372, 95% CI: 0.8070-0.8673) was achieved when all AMD features present at base line were included. Conclusions: Highest turnover rates from intermediate to late AMD were provided by the AREDS simplified scale and the Rotterdam classification. The 3-Continent harmonization classification showed the most stable progression. All features, especially drusenarea,contribute to late AMD prediction. Translational Relevance: Findings will help stakeholders select appropriate classification systems for screening,deep learning algorithms, or trials

A Deep Learning Model for Segmentation of Geographic Atrophy to Study Its Long-Term Natural History

__Purpose:__ To develop and validate a deep learning model for the automatic segmentation of geographic atrophy (GA) using color fundus images (CFIs) and its application to study the growth rate of GA. __Design:__ Prospective, multicenter, natural history study with up to 15 years of follow-up. __Participants:__ Four hundred nine CFIs of 238 eyes with GA from the Rotterdam Study (RS) and Blue Mountain Eye Study (BMES) for model development, and 3589 CFIs of 376 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. __Methods:__ A deep learning model based on an ensemble of encoder–decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated, in consensus, GA in CFIs from the RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was applied further to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and the GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. __Main Outcome Measures:__ Automatically segmented GA and GA growth rate. __Results:__ The model obtained an average Dice coefficient of 0.72±0.26 on the BMES and RS set while comparing the automatically segmented GA area with the graders’ manual delineations. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders’ consensus measures. Nine automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement, perimeter, and circularity) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of approximately 12 mm2, after which growth rate stabilizes or decreases. __Conclusions:__ The deep learning model allowed for fully automatic and robust segmentation of GA on CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate

Measurement of Mass and Width of the W Boson at LEP

We report on measurements of the mass and total decay width of the W boson with the L3 detector at LEP. W-pair events produced in $\mathrm{e^+e^-}$ interactions between 161 GeV and 183 GeV centre-of-mass energy are selected in a data sample corresponding to a total luminosity of 76.7 pb$^{-1}$. Combining all final states in W-pair production, the mass and total decay width of the W boson are determined to be $\mathrm{M_W}=80.61\pm0.15$ GeV and $\Gamma_{\mathrm{W}}=1.97\pm0.38$ GeV, respectively

Search for Heavy Neutral and Charged Leptons in e+^+e−^- Annihilation at s\sqrt{s} = 183 and 189 GeV

A search for unstable neutral and charged heavy leptons as well as for stable charged heavy leptons is performed at center-of-mass energies $\sqrt{s}$ = 183 and 189 GeV with the L3 detector at LEP. No evidence for their existence is found. We exclude neutral heavy leptons which couple to the electron, muon or tau family, of the Dirac type for masses below 92.4, 93.3 and 83.3 GeV, and of the Majorana type for masses below 81.8, 84.1 and 73.5 GeV, respectively. We exclude unstable charged heavy leptons for masses below 93.9 GeV for a wide range of the associated neutral heavy lepton mass. If the unstable charged heavy lepton decays to a light neutrino, we exclude masses below 92.4 GeV. The production of stable charged heavy leptons with mass less than 93.5 GeV is also excluded

Measurement of an Elongation of the Pion Source in Z Decays

We measure Bose-Einstein correlations between like-sign charged pion pairs in hadronic Z decays with the L3 detector at LEP. The analysis is performed in three dimensions in the longitudinal center-of-mass system. The pion source is found to be elongated along the thrust axis with a ratio of transverse to longitudinal radius of $0.81\pm 0.02 ^{+0.03}_{-0.19}$

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 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