The use of prognostic scores for causal inference with general treatment regimes

In nonrandomised studies, inferring causal effects requires appropriate methods for addressing confounding bias. Although it is common to adopt propensity score analysis to this purpose, prognostic score analysis has recently been proposed as an alternative strategy. While both approaches were originally introduced to estimate causal effects for binary interventions, the theory of propensity score has since been extended to the case of general treatment regimes. Indeed, many treatments are not assigned in a binary fashion and require a certain extent of dosing. Hence, researchers may often be interested in estimating treatment effects across multiple exposures. To the best of our knowledge, the prognostic score analysis has not been yet generalised to this case. In this article, we describe the theory of prognostic scores for causal inference with general treatment regimes. Our methods can be applied to compare multiple treatments using nonrandomised data, a topic of great relevance in contemporary evaluations of clinical interventions. We propose estimators for the average treatment effects in different populations of interest, the validity of which is assessed through a series of simulations. Finally, we present an illustrative case in which we estimate the effect of the delay to Aspirin administration on a composite outcome of death or dependence at 6 months in stroke patients

Addressing missing data in the estimation of time-varying treatments in comparative effectiveness research

Comparative effectiveness research is often concerned with evaluating treatment strategies sustained over time, that is, time-varying treatments. Inverse probability weighting (IPW) is often used to address the time-varying confounding by re-weighting the sample according to the probability of treatment receipt at each time point. IPW can also be used to address any missing data by re-weighting individuals according to the probability of observing the data. The combination of these two distinct sets of weights may lead to inefficient estimates of treatment effects due to potentially highly variable total weights. Alternatively, multiple imputation (MI) can be used to address the missing data by replacing each missing observation with a set of plausible values drawn from the posterior predictive distribution of the missing data given the observed data. Recent studies have compared IPW and MI for addressing the missing data in the evaluation of time-varying treatments, but they focused on missing confounders and monotone missing data patterns. This article assesses the relative advantages of MI and IPW to address missing data in both outcomes and confounders measured over time, and across monotone and non-monotone missing data settings. Through a comprehensive simulation study, we find that MI consistently provided low bias and more precise estimates compared to IPW across a wide range of scenarios. We illustrate the implications of method choice in an evaluation of biologic drugs for patients with severe rheumatoid arthritis, using the US National Databank for Rheumatic Diseases, in which 25% of participants had missing health outcomes or time-varying confounders

Model for the architecture of caveolae based on a flexible, net-like assembly of Cavin1 and Caveolin discs.

Caveolae are invaginated plasma membrane domains involved in mechanosensing, signaling, endocytosis, and membrane homeostasis. Oligomers of membrane-embedded caveolins and peripherally attached cavins form the caveolar coat whose structure has remained elusive. Here, purified Cavin1 60S complexes were analyzed structurally in solution and after liposome reconstitution by electron cryotomography. Cavin1 adopted a flexible, net-like protein mesh able to form polyhedral lattices on phosphatidylserine-containing vesicles. Mutating the two coiled-coil domains in Cavin1 revealed that they mediate distinct assembly steps during 60S complex formation. The organization of the cavin coat corresponded to a polyhedral nano-net held together by coiled-coil segments. Positive residues around the C-terminal coiled-coil domain were required for membrane binding. Purified caveolin 8S oligomers assumed disc-shaped arrangements of sizes that are consistent with the discs occupying the faces in the caveolar polyhedra. Polygonal caveolar membrane profiles were revealed in tomograms of native caveolae inside cells. We propose a model with a regular dodecahedron as structural basis for the caveolae architecture

Micro-Capsules in Shear Flow

This paper deals with flow-induced shape transitions of elastic capsules. The state of the art concerning both theory and experiments is briefly reviewed starting with dynamically induced small deformation of initially spherical capsules and the formation of wrinkles on polymerized membranes. Initially non-spherical capsules show tumbling and tank-treading motion in shear flow. Theoretical descriptions of the transition between these two types of motion assuming a fixed shape are at variance with the full capsule dynamics obtained numerically. To resolve the discrepancy, we expand the exact equations of motion for small deformations and find that shape changes play a dominant role. We classify the dynamical phase transitions and obtain numerical and analytical results for the phase boundaries as a function of viscosity contrast, shear and elongational flow rate. We conclude with perspectives on timedependent flow, on shear-induced unbinding from surfaces, on the role of thermal fluctuations, and on applying the concepts of stochastic thermodynamics to these systems.Comment: 34 pages, 15 figure

Cluster randomized trials with a small number of clusters: which analyses should be used?

BACKGROUND: Cluster randomized trials (CRTs) are increasingly used to assess the effectiveness of health interventions. Three main analysis approaches are: cluster-level analyses, mixed-models and generalized estimating equations (GEEs). Mixed models and GEEs can lead to inflated type I error rates with a small number of clusters, and numerous small-sample corrections have been proposed to circumvent this problem. However, the impact of these methods on power is still unclear. METHODS: We performed a simulation study to assess the performance of 12 analysis approaches for CRTs with a continuous outcome and 40 or fewer clusters. These included weighted and unweighted cluster-level analyses, mixed-effects models with different degree-of-freedom corrections, and GEEs with and without a small-sample correction. We assessed these approaches across different values of the intraclass correlation coefficient (ICC), numbers of clusters and variability in cluster sizes. RESULTS: Unweighted and variance-weighted cluster-level analysis, mixed models with degree-of-freedom corrections, and GEE with a small-sample correction all maintained the type I error rate at or below 5% across most scenarios, whereas uncorrected approaches lead to inflated type I error rates. However, these analyses had low power (below 50% in some scenarios) when fewer than 20 clusters were randomized, with none reaching the expected 80% power. CONCLUSIONS: Small-sample corrections or variance-weighted cluster-level analyses are recommended for the analysis of continuous outcomes in CRTs with a small number of clusters. The use of these corrections should be incorporated into the sample size calculation to prevent studies from being underpowered

Timeline cluster: a graphical tool to identify risk of bias in cluster randomised trials

Robust evidence of the effectiveness of interventions relating to policy, practice, and organisation of healthcare often comes from well conducted cluster randomised trials. Such trials are, however, prone to recruitment bias depending on whether participants are recruited before the randomisation of clusters and whether the recruiter is blinded to the allocation status. In most cases, participants and trial staff cannot be blinded to the intervention, which might lead to performance and detection bias. Unfortunately, cluster trial reports often do not provide a clear description of the timing of trial processes and blinding, and these aspects are not covered by current reporting tools. This article proposes a graphical tool depicting the time sequence of steps and blinding status in cluster randomised trials. The tool might be helpful at both the protocol and the report writing stages to clarify the process and to help identify potential bias in cluster randomised trials

Physical properties of ESA Rosetta target asteroid (21) Lutetia: Shape and flyby geometry

Aims. We determine the physical properties (spin state and shape) of asteroid (21) Lutetia, target of the ESA Rosetta mission, to help in preparing for observations during the flyby on 2010 July 10 by predicting the orientation of Lutetia as seen from Rosetta. Methods. We use our novel KOALA inversion algorithm to determine the physical properties of asteroids from a combination of optical lightcurves, disk-resolved images, and stellar occultations, although the latter are not available for (21) Lutetia. Results. We find the spin axis of (21) Lutetia to lie within 5 degrees of ({\lambda} = 52 deg., {\beta} = -6 deg.) in Ecliptic J2000 reference frame (equatorial {\alpha} = 52 deg., {\delta} = +12 deg.), and determine an improved sidereal period of 8.168 270 \pm 0.000 001 h. This pole solution implies the southern hemisphere of Lutetia will be in "seasonal" shadow at the time of the flyby. The apparent cross-section of Lutetia is triangular as seen "pole-on" and more rectangular as seen "equator-on". The best-fit model suggests the presence of several concavities. The largest of these is close to the north pole and may be associated with large impacts.Comment: 17 pages, 5 figures, 3 tables, submitted to Astronomy and Astrophysic

Correction to: The Thermal, Mechanical, Structural, and Dielectric Properties of Cometary Nuclei After Rosetta

International audienc

The Thermal, Mechanical, Structural, and Dielectric Properties of Cometary Nuclei After Rosetta

The physical properties of cometary nuclei observed today relate to their complex history and help to constrain their formation and evolution. In this article, we review some of the main physical properties of cometary nuclei and focus in particular on the thermal, mechanical, structural and dielectric properties, emphasising the progress made during the Rosetta mission. Comets have a low density of 480±220 kgm−3 and a low permittivity of 1.9–2.0, consistent with a high porosity of 70–80%, are weak with a very low global tensile strength −1m−2s−1/2 that allowed them to preserve highly volatiles species (e.g. CO, CO2, CH4, N2) into their interior since their formation. As revealed by 67P/Churyumov-Gerasimenko, the above physical properties vary across the nucleus, spatially at its surface but also with depth. The broad picture is that the bulk of the nucleus consists of a weakly bonded, rather homogeneous material that preserved primordial properties under a thin shell of processed material, and possibly covered by a granular material; this cover might in places reach a thickness of several meters. The properties of the top layer (the first meter) are not representative of that of the bulk nucleus. More globally, strong nucleus heterogeneities at a scale of a few meters are ruled out on 67P’s small lobe