Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part I: main content

Dynamic treatment regimes are set rules for sequential decision making based on patient covariate history. Observational studies are well suited for the investigation of the effects of dynamic treatment regimes because of the variability in treatment decisions found in them. This variability exists because different physicians make different decisions in the face of similar patient histories. In this article we describe an approach to estimate the optimal dynamic treatment regime among a set of enforceable regimes. This set is comprised by regimes defined by simple rules based on a subset of past information. The regimes in the set are indexed by a Euclidean vector. The optimal regime is the one that maximizes the expected counterfactual utility over all regimes in the set. We discuss assumptions under which it is possible to identify the optimal regime from observational longitudinal data. Murphy et al. (2001) developed efficient augmented inverse probability weighted estimators of the expected utility of one fixed regime. Our methods are based on an extension of the marginal structural mean model of Robins (1998, 1999) which incorporate the estimation ideas of Murphy et al. (2001). Our models, which we call dynamic regime marginal structural mean models, are specially suitable for estimating the optimal treatment regime in a moderately small class of enforceable regimes of interest. We consider both parametric and semiparametric dynamic regime marginal structural models. We discuss locally efficient, double-robust estimation of the model parameters and of the index of the optimal treatment regime in the set. In a companion paper in this issue of the journal we provide proofs of the main results.

Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part II: proofs of results

In this companion article to "Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes, Part I: Main Content" [Orellana, Rotnitzky and Robins (2010), IJB, Vol. 6, Iss. 2, Art. 7] we present (i) proofs of the claims in that paper, (ii) a proposal for the computation of a confidence set for the optimal index when this lies in a finite set, and (iii) an example to aid the interpretation of the positivity assumption.

Semiparametric Theory for Causal Mediation Analysis: efficiency bounds, multiple robustness, and sensitivity analysis

Whilst estimation of the marginal (total) causal effect of a point exposure on an outcome is arguably the most common objective of experimental and observational studies in the health and social sciences, in recent years, investigators have also become increasingly interested in mediation analysis. Specifically, upon establishing a non-null total effect of the exposure, investigators routinely wish to make inferences about the direct (indirect) pathway of the effect of the exposure not through (through) a mediator variable that occurs subsequently to the exposure and prior to the outcome. Although powerful semiparametric methodologies have been developed to analyze observational studies, that produce double robust and highly efficient estimates of the marginal total causal effect, similar methods for mediation analysis are currently lacking. Thus, this paper develops a general semiparametric framework for obtaining inferences about so-called marginal natural direct and indirect causal effects, while appropriately accounting for a large number of pre-exposure confounding factors for the exposure and the mediator variables. Our analytic framework is particularly appealing, because it gives new insights on issues of efficiency and robustness in the context of mediation analysis. In particular, we propose new multiply robust locally efficient estimators of the marginal natural indirect and direct causal effects, and develop a novel double robust sensitivity analysis framework for the assumption of ignorability of the mediator variable.

Double neutron/proton ratio of nucleon emissions in isotopic reaction systems as a robust probe of nuclear symmetry energy

The double neutron/proton ratio of nucleon emissions taken from two reaction systems using four isotopes of the same element, namely, the neutron/proton ratio in the neutron-rich system over that in the more symmetric system, has the advantage of reducing systematically the influence of the Coulomb force and the normally poor efficiencies of detecting low energy neutrons. The double ratio thus suffers less systematic errors. Within the IBUU04 transport model the double neutron/proton ratio is shown to have about the same sensitivity to the density dependence of nuclear symmetry energy as the single neutron/proton ratio in the neutron-rich system involved. The double neutron/proton ratio is therefore more useful for further constraining the symmetry energy of neutron-rich matter.

Robust tori in a double-waved Hamiltonian model

A Hamiltonian system perturbed by two waves with particular wave numbers can present robust tori, which are barriers created by the vanishing of the perturbed Hamiltonian at some defined positions. When robust tori exist, any trajectory in phase space passing close to them is blocked by emergent invariant curves that prevent the chaotic transport. Our results indicate that the considered particular solution for the two waves Hamiltonian model shows plenty of robust tori blocking radial transport. (C) 2010 Elsevier B.V. All rights reserved.

Robust tori in a double-waved Hamiltonian model

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Double Higgs production at the LHC as a robust test of little Higgs models

We analyze double Higgs boson production at the LHC in the context of Little Higgs models. In double Higgs production, the diagrams involved are directly related to those that cause the cancellation of the quadratic divergence of the Higgs self-energy, so this mode provides a robust prediction for this class of models. We find that in extensions of this model with the inclusion of a so-called T-parity, there is a significant enhancement in the cross sections as compared to the Standard Model. © 2006 American Institute of Physics.

Treatment rationale study design for the MetLung trial : a randomized, double-blind phase III study of onartuzumab (MetMAb) in combination with erlotinib versus erlotinib alone in patients who have received standard chemotherapy for stage IIIB or IV met-positive non-small-cell lung cancer

We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC. © 2012 Elsevier Inc. All Rights Reserved.

Elucidation of double bond position in unsaturated lipids by ozone electrospray ionization mass spectrometry

The position(s) of carbon-carbon double bonds within lipids can dramatically affect their structure and reactivity and thus has a direct bearing on biological function. Commonly employed mass spectrometric approaches to the characterization of complex lipids, however, fail to localize sites of unsaturation within the molecular structure and thus cannot distinguish naturally occurring regioisomers. In a recent communication \[Thomas, M. C.; Mitchell, T. W.; Blanksby, S. J. J. Am. Chem. Soc. 2006, 128, 58-59], we have presented a new technique for the elucidation of double bond position in glycerophospholipids using ozone-induced fragmentation within the source of a conventional electrospray ionization mass spectrometer. Here we report the on-line analysis, using ozone electrospray mass spectrometry (OzESI-MS), of a broad range of common unsaturated lipids including acidic and neutral glycerophospholipids, sphingomyelins, and triacylglycerols. All lipids analyzed are found to form a pair of chemically induced fragment ions diagnostic of the position of each double bond(s) regardless of the polarity, the number of charges, or the adduction (e.g., \[M - H](-), \[M - 2H](2-), \[M + H](+), \[M + Na](+), \[M + NH4](+)). The ability of OzESI-MS to distinguish lipids that differ only in the position of the double bonds is demonstrated using the glycerophosphocholine standards, GPCho(9Z-18:1/9Z-18:1) and GPCho(6Z-18:1/6Z-18:1). While these regioisomers cannot be differentiated by their conventional tandem mass spectra, the OzESI-MS spectra reveal abundant fragment ions of distinctive mass-to-charge ratio (m/z). The approach is found to be sufficiently robust to be used in conjunction with the m/z 184 precursor ion scans commonly employed for the identification of phosphocholine-containing lipids in shotgun lipidomic analyses. This tandem OzESI-MS approach was used, in conjunction with conventional tandem mass spectral analysis, for the structural characterization of an unknown sphingolipid in a crude lipid extract obtained from a human lens. The OzESI-MS data confirm the presence of two regioisomers, namely, SM(d18:0/15Z-24:1) and SM(d18:0/17Z-24:1), and suggest the possible presence of a third isomer, SM(d18:0/19Z-24:1), in lower abundance. The data presented herein demonstrate that OzESI-MS is a broadly applicable, on-line approach for structure determination and, when used in conjunction with established tandem mass spectrometric methods, can provide near complete structural characterization of a range of important lipid classes. As such, OzESI-MS may provide important new insight into the molecular diversity of naturally occurring lipids.

L-dopa modulates functional connectivity in striatal cognitive and motor networks: A double-blind placebo-controlled study

Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 healthy young adults.Weexamined the FC of 6 striatal regions of interest (ROIs) previously shown to elicit networks known to be associated with motivational, cognitive and motor subdivisions of the caudate and putamen (Di Martino et al., 2008). In addition to replicating the previously demonstrated patterns of striatal FC, we observed robust effects of L-dopa. Specifically, L-dopa increased FC in motor pathways connecting the putamen ROIs with the cerebellum and brainstem. Although L-dopa also increased FC between the inferior ventral striatum and ventrolateral prefrontal cortex, it disrupted ventral striatal and dorsal caudate FC with the default mode network. These alterations in FC are consistent with studies that have demonstrated dopaminergic modulation of cognitive and motor striatal networks in healthy participants. Recent studies have demonstrated altered resting state FC in several conditions believed to be characterized by abnormal dopaminergic neurotransmission. Our findings suggest that the application of similar experimental pharmacological manipulations in such populations may further our understanding of the role of dopaminergic neurotransmission in those conditions.

An Efficient Robust Algorithm for the Surface-Potential Calculation of Independent DG MOSFET

Although the recently proposed single-implicit-equation-based input voltage equations (IVEs) for the independent double-gate (IDG) MOSFET promise faster computation time than the earlier proposed coupled-equations-based IVEs, it is not clear how those equations could be solved inside a circuit simulator as the conventional Newton-Raphson (NR)-based root finding method will not always converge due to the presence of discontinuity at the G-zero point (GZP) and nonremovable singularities in the trigonometric IVE. In this paper, we propose a unique algorithm to solve those IVEs, which combines the Ridders algorithm with the NR-based technique in order to provide assured convergence for any bias conditions. Studying the IDG MOSFET operation carefully, we apply an optimized initial guess to the NR component and a minimized solution space to the Ridders component in order to achieve rapid convergence, which is very important for circuit simulation. To reduce the computation budget further, we propose a new closed-form solution of the IVEs in the near vicinity of the GZP. The proposed algorithm is tested with different device parameters in the extended range of bias conditions and successfully implemented in a commercial circuit simulator through its Verilog-A interface.

Swam Intelligent Based Inverse Model for Laboratory Double Reservoir Diffusion Experiments

Theoretical approaches are of fundamental importance to predict the potential impact of waste disposal facilities on ground water contamination. Appropriate design parameters are, in general, estimated by fitting the theoretical models to a field monitoring or laboratory experimental data. Double-reservoir diffusion (Transient Through-Diffusion) experiments are generally conducted in the laboratory to estimate the mass transport parameters of the proposed barrier material. These design parameters are estimated by manual parameter adjusting techniques (also called eye-fitting) like Pollute. In this work an automated inverse model is developed to estimate the mass transport parameters from transient through-diffusion experimental data. The proposed inverse model uses particle swarm optimization (PSO) algorithm which is based on the social behaviour of animals for finding their food sources. Finite difference numerical solution of the transient through-diffusion mathematical model is integrated with the PSO algorithm to solve the inverse problem of parameter estimation.The working principle of the new solver is demonstrated by estimating mass transport parameters from the published transient through-diffusion experimental data. The estimated values are compared with the values obtained by existing procedure. The present technique is robust and efficient. The mass transport parameters are obtained with a very good precision in less time

Processing of DNA double-stranded breaks and intermediates of recombination and repair by saccharomyces cerevisiae Mre11 and its stimulation by Rad50, Xrs2, and Sae2 proteins

Saccharomyces cerevisiae RAD50, MRE11, and XRS2 genes are essential for telomere length maintenance, cell cycle checkpoint signaling, meiotic recombination, and DNA double-stranded break (DSB) repair via nonhomologous end joining and homologous recombination. The DSB repair pathways that draw upon Mre11-Rad50-Xrs2 subunits are complex, so their mechanistic features remain poorly understood. Moreover, the molecular basis of DSB end resection in yeast mre11-nuclease deficient mutants and Mre11 nuclease-independent activation of ATM in mammals remains unknown and adds a new dimension to many unanswered questions about the mechanism of DSB repair. Here, we demonstrate that S. cerevisiae Mre11 (ScMre11) exhibits higher binding affinity for single-over double-stranded DNA and intermediates of recombination and repair and catalyzes robust unwinding of substrates possessing a 3' single-stranded DNA overhang but not of 5' overhangs or blunt-ended DNA fragments. Additional evidence disclosed that ScMre11 nuclease activity is dispensable for its DNA binding and unwinding activity, thus uncovering the molecular basis underlying DSB end processing in mre11 nuclease deficient mutants. Significantly, Rad50, Xrs2, and Sae2 potentiate the DNA unwinding activity of Mre11, thus underscoring functional interaction among the components of DSB end repair machinery. Our results also show that ScMre11 by itself binds to DSB ends, then promotes end bridging of duplex DNA, and directly interacts with Sae2. We discuss the implications of these results in the context of an alternative mechanism for DSB end processing and the generation of single-stranded DNA for DNA repair and homologous recombination.

Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions

Mitochondrial DNA (mtDNA) deletions are associated with various mitochondrial disorders. The deletions identified in humans are flanked by short, directly repeated mitochondrial DNA sequences; however, the mechanism of such DNA rearrangements has yet to be elucidated. In contrast to nuclear DNA (nDNA), mtDNA is more exposed to oxidative damage, which may result in double-strand breaks (DSBs). Although DSB repair in nDNA is well studied, repair mechanisms in mitochondria are not characterized. In the present study, we investigate the mechanisms of DSB repair in mitochondria using in vitro and ex vivo assays. Whereas classical NHEJ (C-NHEJ) is undetectable, microhomology-mediated alternative NHEJ efficiently repairs DSBs in mitochondria. Of interest, robust microhomology-mediated end joining (MMEJ) was observed with DNA substrates bearing 5-, 8-, 10-, 13-, 16-, 19-, and 22-nt microhomology. Furthermore, MMEJ efficiency was enhanced with an increase in the length of homology. Western blotting, immunoprecipitation, and protein inhibition assays suggest the involvement of CtIP, FEN1, MRE11, and PARP1 in mitochondrial MMEJ. Knock-down studies, in conjunction with other experiments, demonstrated that DNA ligase III, but not ligase IV or ligase I, is primarily responsible for the final sealing of DSBs during mitochondrial MMEJ. These observations highlight the central role of MMEJ in maintenance of mammalian mitochondrial genome integrity and is likely relevant for deletions observed in many human mitochondrial disorders.

Robust speed control for a variable speed wind turbine

Modern wind turbines are designed in order to work in variable speed opera-tions. To perform this task, these turbines are provided with adjustable speed generators, like the double feed induction generator (DFIG). One of the main advantages of adjustable speed generators is improving the system efficiency compared with _xed speed generators, because turbine speed can be adjusted as a function of wind speed in order to maximize the output power. However, this system requires a suitable speed controller in order to track the optimal reference speed of the wind turbine. In this work, a sliding mode control for variable speed wind turbines is proposed. The proposed design also uses the vector oriented control theory in order to simplify the DFIG dynamical equations. The stability analysis of the proposed controller has been carried out under wind variations and pa-rameter uncertainties using the Lyapunov stability theory. Finally, the simulated results show on the one hand that the proposed controller provides a high-performance dynamic behavior, and on the other hand that this scheme is robust with respect to parameter uncertainties and wind speed variations, which usually appear in real systems.